Substituted azepino[4,5b]indoline derivatives

ABSTRACT

The invention provides compounds of Formula (I):  
                 
 
     wherein R 1 -R 4 , p and q have any of the values described in the specification, as well as pharmaceutical salts thereof, and pharmaceutical compositions containing such compounds or salts. The compounds and salts are 5-HT ligands and are useful for treating diseases, disorders, and/or conditions in a mammal wherein activity of a 5-HT receptor is implicated. The compounds and salts are particularly useful for treating diseases of the central nervous system.

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority from U.S. ProvisionalApplication No. 60/234,376, filed Sep. 20, 2000; U.S. ProvisionalApplication No. 60/266,047, filed Feb. 1, 2001; and U.S. ProvisionalApplication No. 60/301,964, filed Jun. 29, 2001.

BACKGROUND OF THE INVENTION

[0002] 1. Field of the Invention

[0003] The present invention generally relates to a series of compounds,to pharmaceutical compositions containing the compounds, and to use ofthe compounds and compositions as therapeutic agents. More specifically,compounds of the present invention are octahydroazepinoindole compounds.These compounds are serotonin receptor (5-HT) ligands and are useful fortreating diseases, disorders, and conditions wherein modulation of theactivity of serotonin receptors (5-HT) is desired (e.g. anxiety,depression or obesity).

[0004] 2. Brief Description of Related Technology

[0005] Serotonin has been implicated in a number of diseases, disorders,and conditions that originate in the central nervous system, includingdiseases, disorders, and conditions related to, for example, sleeping,eating, perceiving pain, controlling body temperature, controlling bloodpressure, depression, anxiety, and schizophrenia. Serotonin also playsan important role in peripheral systems, such as the gastrointestinalsystem, where it has been found to mediate a variety of contractile,secretory, and electrophysiologic effects.

[0006] Because of the broad distribution of serotonin within the body, aheightened interest exists for drugs that affect serotonergic systems.In particular, agonists, partial agonists, and antagonists ofserotonergic systems are of interest for the treatment of a wide rangeof disorders, including anxiety, depression, hypertension, migraine,obesity, compulsive disorders, schizophrenia, autism, neurodegenerativedisorders (e.g., Alzheimer's disease, Parkinsonism, and Huntington'schorea), and chemotherapy-induced vomiting.

[0007] The major classes of serotonin receptors (5-HT₁₋₇) containfourteen to eighteen separate receptors that have been formallyclassified. See Glennon, et al., Neuroscience and Behavioral Reviews,1990, 14, 35; and D. Hoyer, et al. Pharmacol. Rev. 1994, 46, 157-203.

[0008] For example, the 5-HT₂ family of receptors contains 5-HT_(2A),5-HT_(2B), and 5-HT_(2C) subtypes, which have been grouped together onthe basis of primary structure, secondary messenger system, andoperational profile. All three 5-HT₂ subtypes are G-protein coupled,activate phospholipase C as a principal transduction mechanism, andcontain a seven-transmembrane domain structure. There are distinctdifferences in the distribution of the three 5-HT₂ subtypes in a mammal.The 5-HT_(2B) and 5-HT_(2A) receptors are widely distributed in theperipheral nervous system, while the 5-HT_(2C) receptor has been foundonly in the central nervous system, being highly expressed in manyregions of the human brain. See G. Baxter, et al. Trends in Pharmacol.Sci. 1995, 16, 105-110.

[0009] Subtype 5-HT_(2A) has been associated with effects includingvasoconstriction, platelet aggregation, and bronchoconstriction, whilesubtype 5-HT_(2C) has been associated with diseases that includedepression, anxiety, obsessive compulsive disorder, panic disorders,phobias, psychiatric syndromes, and obesity. Very little is known aboutthe pharmocologic role of the 5-HT_(2B) receptor. See F. Jenck, et al.,Exp. Opin. Invest. Drugs, 1998, 7, 1587-1599; M. Bos, et al., J. Med.Chem., 1997, 40, 2762-2769; J. R. Martin, et al., The Journal ofPharmacology and Experimental Therapeutics, 1998, 286, 913-924; S. M.Bromidge, et al., J. Med. Chem., 1998, 41,1598-1612; G. A. Kennett,Drugs, 1998, 1, 4, 456-470; and A. Dekeyne, et al., Neuropharmacology,1999, 38, 415-423.

[0010] U.S. Pat. Nos. 3,553,232 and 3,622,673 disclose4-(1,4,5,6-tetrahydroazepine[4,5-b]indole-3(2H)-yl) butyrophenones thatare reported to be useful in the treatment of mental or emotionaldisorders.

[0011] N. M. Sharkova et al., Khim. Geterotsikl. Soedin., 1969, 1,88-90; report certain specific azepino[4,5-b]indoline compounds of theformula

[0012] wherein R is hydrogen, nitroso, or amino. No biological activitywas reported for the compounds.

[0013] G. N. Artemenko et al., Farmakol. Toksikol, 1972, 35, 3, 274-280report certain specific azepino[4,5-b]indoline compounds of the formula

[0014] wherein R₁ is hydrogen or 3-(N,N-dimethylamino)propyl; and R ishydrogen or methyl. The compounds were reported to have antipressantactivity similar to amitriptyline.

[0015] U.S. Pat. Nos. 3,652,588, 3,676,558, and 3,839,357 disclose6-alkyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles and aneroxigeniccompounds thereof that are reportedly useful to tranquilize andotherwise sedate mammals or suppress hunger in mammals.

[0016] JP Public Patent Disclosure Bulletin Number 63-163347 disclosescompounds that are reported to prevent fading of organic coloringsubstances.

[0017] International Patent Application Publication Number WO 01/0573 A1discloses 9-arylsulfone-1,2,3,4,5,6-hexahydroazepino[4,5-b]indoles thatare reported to be useful for treating depression, obesity, and otherCNS disorders.

[0018] Despite the teachings in the above-cited publications, thereremains a need for pharmaceutical agents that are useful in treating avariety of diseases, disorders, and conditions that are associated withserotonin (5-HT) receptors.

SUMMARY OF THE INVENTION

[0019] Generally, the present invention is directed to methods andcompositions useful in treating a disease, disorder, and/or condition ina mammal wherein a 5-HT receptor is implicated, and modulation of a 5-HTfunction is desired, by using a novel compound disclosed herein.

[0020] In accordance with the present invention, novel compounds whichdemonstrate useful biological activity, and particularly activity as5-HT receptor ligands, are provided. More specifically, the inventionprovides a compound of Formula (I):

[0021] wherein

[0022] R¹ is selected from the group consisting of hydrogen, C₁₋₈alkyl,and C₁₋₈hydrocarbylene Ar;

[0023] each R², independently, is selected from the group consisting ofC₁₋₈alkyl, and OH;

[0024] R³ is hydrogen, C₁₋₈alkyl, Ar, Het, R⁷C(═O)—, R⁷OC(═O)—,R⁵R⁶NC(═O)—, R⁷C(═S)—, R⁷SC(═O)—, R⁵R⁶NC(═S)—, R⁷SO₂—, R⁵R⁶NSO₂—,R⁷S(═O)—, R⁵R⁶NS(═O)—, R^(c)C₁₋₈hydrocarbylene-, or R^(c)₁₋₈hydrocarbyleneC(═O)—;

[0025] each R⁴, independently, is selected from the group consisting ofAr, C₁₋₈alkyl, ArO—, C₁₋₈alkoxy, Het, halo, OH, CN, NO₂, CF₃, CF₃O,NR^(a)R^(b), N═CR^(a)R^(b), R⁷S, C₁₋₈hydrocarbyleneAr, andC₁₋₈hydrocarbyleneOR^(a);

[0026] each R⁵ and R⁶ is independently hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl,C₂₋₈alkynyl, haloC₁₋₈alkyl, C₃₋₈cycloalkenyl, Ar, or—C₁₋₈hydrocarbyleneAr; or R⁵ and R⁶ together with the nitrogen to whichthey are attached form a pyrrolidino, piperidino, morpholino, orthiomorpholino ring;

[0027] each R⁷ is independently hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl,C₂₋₈alkynyl, haloC₁₋₈alkyl, C₃₋₈cycloalkenyl, Ar, or—C₁₋₈hydrocarbyleneAr;

[0028] R^(a) and R^(b), independently, are selected from the groupconsisting of hydrogen, C₁₋₈alkyl, Ar, C₁₋₃hydrocarbyleneAr, SO₂Ar,SO₂C₁₋₄ alkyl, (C₃₋₈cycloalkyl)C₁₋₈alkyl, and Het;

[0029] R^(c) is Ar, Het, R⁷CO₂—, R⁷C(═O)—, R⁷OC(═O)—, R⁷O—,R⁷C₁₋₈alkyleneO—, R⁷S—, R⁷C(═S)—, R⁷S(═O)—, R⁷S(═O)₂—, R⁷SC(—O)—,R⁷C(═O)N(R⁷)—, R⁷C(═S)N(R⁷)—, R⁵R⁶N—, R⁵R⁶NC(═O)—, R⁵R⁶NC(═S)—,R⁵R⁶NS(═O)—, R⁵R⁶NSO₂—, R⁷S(═O)N(R⁷)—, R⁷SO₂N(R⁷)—, or R⁷N(R⁷)C(═O)N(R⁷)—;

[0030] each Ar is independently aryl or heteroaryl;

[0031] p is 0, 1, 2, 3, or 4; and

[0032] q is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10;

[0033] wherein any Ar of R¹, R³-R⁷, R^(a), R^(b) and R^(c) is optionallysubstituted with one or more (e.g. 1, 2, 3, 4, or 5) substituentsindependently selected from halo, CN, NO₂, OR^(e), methylenedioxy,ethylenedioxy, CF₃, OCF₃, SR^(e), SO₂R^(e), NR^(f)R^(g), CONR^(f)R^(g),COR^(e), R^(e), and C₁₋₈hydrocarbyleneR^(d);

[0034] each R^(d) is independently hydroxy, C₁₋₈alkoxy, cyano, SR^(h),or C(═O)R^(h);

[0035] each R^(e) is independently selected from the group consisting ofhydrogen, C₁₋₈alkyl, Ar, C₁₋₃hydrocarbyleneAr, SO₂Ar, SO₂C₁₋₄ alkyl,(C₃₋₈cycloalkyl)C₁₋₈alkyl, and Het; wherein any Ar of R^(e) isoptionally substituted with one or more (e.g. 1, 2, 3, 4, or 5)substituents independently selected from halo, CN, NO₂, OR^(d),methylenedioxy, ethylenedioxy, CF₃, OCF₃, SR^(f), SO₂R^(f), NR^(f)R^(g),CONR^(f)R^(g), COR^(f), R^(f), and C₁₋₈hydrocarbyleneR^(d);

[0036] each R^(f) and R^(g), is independently selected from the groupconsisting of hydrogen, C₁₋₈alkyl, Ar, C₁₋₃hydrocarbyleneAr, SO₂Ar,SO₂C₁₋₄ alkyl, (C₃₋₈cycloalkyl)C₁₋₈alkyl, and Het; and

[0037] each R^(h) is independently hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl,C₂₋₈alkynyl, haloC₁₋₈alkyl, C₃₋₈cycloalkenyl, phenyl, or—C₁₋₈hydrocarbylene(phenyl);

[0038] or a pharmaceutically acceptable salt thereof.

[0039] Preferably for a compound of Formula (I), when

[0040] (a) R¹ is methyl; and

[0041] (b) R³ is hydrogen or —(CH₂)₃NR⁵R⁶, wherein R⁵ and R⁶, are eachmethyl;

[0042] then p and q are not each 0.

[0043] More preferably, for a compound of Formula (I), when

[0044] (a) R¹ is methyl; and

[0045] (b) R³ is hydrogen or —(CH₂)₃NR⁵R⁶, wherein R⁵ and R⁶, are eachmethyl;

[0046] then either

[0047] (i) p is not 0 and at least one R⁴ is Ar, ArO—, C₁₋₈alkoxy, Het,halo, OH, CN, NO₂, CF₃, CF₃O, NR^(a)R^(b), N═CR^(a)R^(b), R⁷S,C₁₋₈hydrocarbyleneAr, and C₁₋₈hydrocarbyleneOR^(a); or

[0048] (ii) q is not 0 and at least one R² is OH.

[0049] Even more preferably for a compound of Formula (I), when

[0050] (a) R¹ is hydrogen or C₁₋₈alkyl; and

[0051] (b) R³ is hydrogen, C₁₋₈alkyl, or C₁₋₈hydrocarbyleneNR⁵R⁶,wherein R⁵ and R⁶, are each independently C₁₋₈alkyl;

[0052] then either

[0053] (i) p is not 0 and at least one R⁴ is Ar, ArO—, C₁₋₈alkoxy, Het,halo, OH, CN, NO₂, CF₃, CF₃O, NR^(a)R^(b), N═CR^(a)R^(b), R⁷S,C₁₋₈hydrocarbyleneAr, and C₁₋₈hydrocarbyleneOR^(a); or

[0054] (ii) q is not 0 and at least one R² is OH.

[0055] Another embodiment of the present invention provides apharmaceutical composition comprising a compound of Formula (I), or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable carrier.

[0056] Still another embodiment of the present invention provides amethod of treating a disease, disorder, and/or condition in a mammal(e.g., animal or human), wherein a 5-HT receptor is implicated andmodulation of a 5-HT function is desired. The method comprisesadministering a therapeutically effective amount of a compound ofFormula (I), or a pharmaceutically acceptable salt thereof, to themammal.

[0057] Yet another embodiment of the present invention comprises amethod of modulating 5-HT receptor function with an effective amount ofa compound of Formula (I), or a pharmaceutically acceptable saltthereof.

[0058] A further embodiment of the present invention provides a methodof treating or preventing diseases, disorders, and/or conditions of thecentral nervous system. The method comprises administering atherapeutically effective amount of a compound of Formula (I), or apharmaceutically acceptable salt thereof, to the mammal.

[0059] Specific diseases, disorders, and/or conditions for whichcompounds of Formula (I) may have activity include, but are not limitedto, obesity, depression, epilepsy, anxiety, Alzheimers disease,withdrawal from drug abuse, schizophrenia, schizophreniform disorder,schizoaffective disorder, delusional disorder, a stress related disease(e.g., general anxiety disorder), panic disorder, a phobia, obsessivecompulsive disorder, post-traumatic-stress syndrome, immune systemdepression, a stress induced problem with the urinary, gastrointestinalor cardiovascular system (e.g., stress incontinence), neurodegenerativedisorders, autism, chemotherapy-induced vomiting, hypertension, migraineheadaches, cluster headaches, sexual dysfunction in a mammal (e.g., ahuman), addictive disorder and withdrawal syndrome, an adjustmentdisorder, an age-associated learning and mental disorder, anorexianervosa, apathy, an attention-deficit disorder due to general medicalconditions, attention-deficit hyperactivity disorder, behavioraldisturbance (including agitation in conditions associated withdiminished cognition, e.g., dementia, mental retardation or delirium),bipolar disorder, bulimia nervosa, chronic fatigue syndrome, conductdisorder, cyclothymic disorder, dysthymic disorder, fibromyalgia andother somatoform disorders, generalized anxiety disorder, an inhalationdisorder, an intoxication disorder, movement disorder (e.g.,Huntington's disease or Tardive Dyskinesia), oppositional defiantdisorder, peripheral neuropathy, post-traumatic stress disorder,premenstrual dysphoric disorder, a psychotic disorder (brief and longduration disorders and psychotic disorder due to medical condition),mood disorder (major depressive or bipolar disorder with psychoticfeatures) seasonal affective disorder, a sleep disorder, a specificdevelopmental disorder, agitation disorder, selective serotonin reuptakeinhibition (SSRI) “poop out” syndrome or a Tic disorder (e.g.,Tourette's syndrome).

[0060] Yet another embodiment of the present invention comprises the useof a compound of Formula (I), or a pharmaceutically acceptable saltthereof, in the preparation of a medicament for treating or preventingdiseases, disorders, and conditions of the central nervous system. Theactivity of 5-HT receptors is implicated in the above diseases of thecentral nervous system.

[0061] The invention also provides synthetic intermediates and processesdisclosed herein, which are useful for preparing compounds of theinvention.

[0062] Compounds of formula (I) are 5-HT ligands. Thus, radiolabeledcompounds of formula (I) are useful as imaging agents for medicaltherapy and diagnosis. Such radiolabeled compounds are also useful aspharmacological tools for studying 5-HT function and activity.Accordingly, the invention also provides a radiolabeled compound offormula (I), or a salt thereof.

[0063] Compounds of formula I can be labeled using techniques which arewell known in the art. For example, a radioisotope can be incorporatedinto the compound or appended to the compound of formula I usingtechniques well known in the art. For example, see Arthur Murry III, D.Lloyd Williams; Organic Synthesis with Isotopes, vol. I and II,Interscience Publishers Inc., N.Y. (1958) and Melvin Calvin et al.Isotopic Carbon John Wiley and Sons Inc., N.Y. (1949). Any radioisotopecapable of being detected can be employed as a label. For example,suitable radioisotopes include: carbon-11, fluorine-18, fluorine-19,iodine-123 and iodine-125. Preferably, a compound of formula I may belabeled by appending one or more radioisotopes of a halogen (e.g.iodine-123) to an aromatic ring, or by alkylating a nitrogen of acompound of formula (I) with a group comprising a phenyl group bearing aradioisotope.

[0064] The invention also provides a radiolabeled compound of formula(I) for use in medical diagnosis or therapy, as well as the use of aradiolabeled compound of formula (I) to prepare a medicamant useful formedical diagnosis or therapy.

[0065] Further aspects and embodiments of the invention may becomeapparent to those skilled in the art from a review of the followingdetailed description, taken in conjunction with the examples and theappended claims. While the invention is susceptible of embodiments invarious forms, described hereafter are specific embodiments of theinvention with the understanding that the present disclosure is intendedas illustrative, and is not intended to limit the invention to thespecific embodiments described herein.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

[0066] FIGS. 1-32 depict reaction schemes for the preparation ofcompounds of the present invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0067] In describing the preferred embodiments, certain terminology hasbeen utilized for the sake of clarity. Such terminology is intended toencompass the recited embodiments as well as all technical equivalentswhich operate in a similar manner for a similar purpose to achieve asimilar result.

[0068] The following definitions are used, unless otherwise described:

[0069] As used herein, the term “alkyl” includes straight chained andbranched hydrocarbon groups containing the indicated number of carbonatoms, typically methyl, ethyl, and straight chain and branched propyland butyl groups. The term “alkyl” also encompasses cycloalkyl, i.e., acyclic C₃-C₈ hydrocarbon group, such as cyclopropyl, cyclobutyl,cyclopentyl, and cyclohexyl. Reference to an individual group or moiety,such as “propyl,” embraces only the straight chain group or moiety. Abranched chain isomer, such as “isopropyl,” is specifically referred to.

[0070] The term “alkoxy” is defined as —OR, wherein R is alkyl.

[0071] The term “halo” is defined herein to include fluoro, chloro,bromo, or iodo. Similarly, the term “halogen” is defined herein toinclude fluorine, chlorine, bromine, and iodine.

[0072] The term “haloalkyl” is defined herein as an alkyl groupsubstituted with one or more halo substituents, either fluoro, chloro,bromo, iodo, or combinations thereof. Similarly, “halocycloalkyl” isdefined as a cycloalkyl group having one or more halo substituents.

[0073] The term “aryl,” alone or in combination, is defined herein as amonocyclic or bicyclic aromatic group (e.g., phenyl or naphthyl) thatcan be unsubstituted or substituted, for example, with one or more, andin particular one to three of the following substituents selected fromthe group consisting of halo, CN, NO₂, CF₃, N₃, C₁₋₆alkyl, OH,NR^(a)R^(b), OC₁₋₆ alkyl, OR^(a), C(═O)NR^(a)R^(b), C(═S)NR^(a)R^(b),tetrazoyl, triazoyl, amidinyl, guanidinyl, thioguanidinyl,cyanoguanadinyl, and aryl. Generally, “aryl” denotes a phenyl group, oran ortho-fused bicyclic carbocyclic group having nine to ten ring atomsin which at least one ring is aromatic (e.g. naphthyl ortetrahydronaphthyl). The term “aryl” also is abbreviated in the variouschemical structures as “Ar.”

[0074] The term “heteroaryl” is defined herein as a monocyclic,bicyclic, or tricyclic ring system containing one, two, or threearomatic rings and containing at least one nitrogen, oxygen, or sulfuratom in an aromatic ring, and which can be unsubstituted or substituted,for example, with one or more, and in particular one to three,substituents, like halo, alkyl, hydroxy, hydroxyalkyl, alkoxy,alkoxyalkyl, haloalkyl, nitro, amino, alkylamino, acylamino, alkylthio,alkylsulfinyl, and alkylsulfonyl. Examples of heteroaryl groups include,but are not limited to, 2H-pyrrolyl, 3H-indolyl, 4H-quinolizinyl,4nH-carbazolyl, acridinyl, benzo[b]thienyl, benzothiazolyl,β-carbolinyl, carbazolyl, chromenyl, cinnaolinyl, dibenzo[b,d]furanyl,furazanyl, furyl, imidazolyl, imidizolyl, indazolyl, indolisinyl,indolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl,isoxazolyl, naphthyridinyl, naptho[2,3-b], oxazolyl, perimidinyl,phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl,phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, pteridinyl,purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl,pyrimidinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl,quinoxalinyl, thiadiazolyl, thianthrenyl, thiazolyl, thienyl, triazolyl,and xanthenyl. In one embodiment the term “heteroaryl” denotes amonocyclic aromatic ring containing five or six ring atoms containingcarbon and 1, 2, 3, or 4 heteroatoms independently selected from thegroup consisting of non-peroxide oxygen, sulfur, and N(Z) wherein Z isabsent or is H, O, C₁₋₄alkyl, phenyl or benzyl. In another embodimentheteroaryl denotes an ortho-fused bicyclic heterocycle of about eight toten ring atoms derived therefrom, particularly a benz-derivative or onederived by fusing a propylene, or tetramethylene diradical thereto.

[0075] The term “Het” generally represents a heterocyclic group,saturated or partially unsaturated, containing at least one heteroatomselected from the group consisting of oxygen, nitrogen, and sulfur, andoptionally substituted with C₁₋₆alkyl or C(═O)OR^(b). Typically “Het” isa monocyclic, bicyclic, or tricyclic group containing one or moreheteroatoms selected from the group consisting of oxygen, nitrogen, andsulfur. A “Het” group also can contain an oxo group (═O) attached to thering. Nonlimiting examples of Het groups include 1,3-dihydrobenzofuran,1,3-dioxolane, 1,4-dioxane, 1,4-dithiane, 2H-pyran, 2-pyrazoline,4H-pyran, chromanyl, imidazolidinyl, imidazolinyl, indolinyl,isochromanyl, isoindolinyl, morpholine, piperazinyl, piperidine,piperidyl, pyrazolidine, pyrazolidinyl, pyrazolinyl, pyrrolidine,pyrroline, quinuclidine, and thiomorpholine.

[0076] The term “alkanoyl” is defined as C(═O)R, wherein R is an alkylgroup as previously defined.

[0077] The term “alkoxycarbonyl” is defined as C(═O)OR, wherein R is analkyl group as previously defined.

[0078] The term “alkylene” refers to a divalent alkyl group having asubstituent. For example, the term “C₁₋₃alkylenearyl” refers to an alkylgroup containing one to three carbon atoms, and substituted with an arylgroup. The term “alkenylene” as used herein is similarly defined, andcontains the indicated number of carbon atoms and a carbon-carbon doublebond, and includes straight chained and branched alkenylene groups, likeethyenylene. The term “alkynylene” as used herein is similary defined,and contains the indicated number of carbon atoms and a carbon-carbontriple bond, and includes straight chained and branched alkynylenegroups, like propynylene.

[0079] The term “hydrocarbylene” refers to alkylene, alkenylene, andalkynylene. For example, the term “C₁₋₃hydrocarbylenearyl” refers to ahydrocarbylene group containing one to three carbon atoms, andsubstituted with an aryl group.

[0080] The term “amino” is defined as —NH₂, and the term “alkylamino” isdefined as —NR₂, wherein at least one R is alkyl and the second R isalkyl or hydrogen. The term “acylamino” is defined as RC(═O)N, wherein Ris alkyl or aryl.

[0081] The term “nitro” is defined as —NO₂.

[0082] The term “trifluoromethyl” is defined as —CF₃.

[0083] The term “trifluoromethoxy” is defined as —OCF₃.

[0084] The term “cyano” is defined as —CN.

[0085] The carbon atom content of various hydrocarbon-containingmoieties is indicated by a prefix designating the minimum and maximumnumber of carbon atoms in the moiety, i.e., the prefix C_(i-j) indicatesa moiety of the integer “i” to the integer “j” carbon atoms, inclusive.Thus, for example, “C₁₋₆ alkyl” refers to alkyls having one to sixcarbon atoms, inclusive.

[0086] Also in the structures herein, for a bond lacking a substituent,the substituent is methyl, for example

[0087] Where no substituent is indicated as attached to a carbon atom ona ring, it is understood that the carbon atom contains the appropriatenumber of hydrogen atoms.

[0088] Abbreviations which are well known to one of ordinary skill inthe art also are used, e.g., “Boc” or “-Boc” for tert-butoxycarbamoyl,“Bz” for benzoyl, “Bn” for benzyl, “Ms” for mesyl, and “Ph” for phenyl.

[0089] Specific and preferred values listed below for groups ormoieties, substituents, and ranges, are for purposes of illustrationonly and do not exclude other defined values or other values within thedefined ranges.

[0090] One embodiment of the present invention provides a compound ofFormula (I):

[0091] wherein:

[0092] R¹ is selected from the group consisting of hydrogen, C₁₋₆ alkyl,and C₁₋₆hydrocarbylenearyl;

[0093] R², independently, is selected from the group consisting of C₁₋₄alkyl, and OH;

[0094] R³ is selected from the group consisting of hydrogen, alkyl,aryl, heteroaryl, C(═O)R^(a), C(═O)OR^(a), C(═O)NR^(a)R^(b),C(═O)SR^(a), C(═S)NR^(a)R^(b), SO₂R^(a), SO₂NR^(a)R^(b), S(═O)R^(a),S(═O)NR^(a)R^(b), C(═O)NR^(a)C₁₋₆hydrocarbyleneOR^(a),C(═O)NR^(a)C₁₋₆hydrocarbyleneHet, C(═O)C₁₋₆hydrocarbylenearyl,C(═O)C₁₋₆-hydrocarbyleneheteroaryl, C₁₋₆hydrocarbylenearyl,C₁₋₆-hydrocarbyleneheteroaryl, C₁₋₆hydrocarbyleneHet,C₁₋₆-hydrocarbyleneC(═O)C₁₋₆hydrocarbylenearyl,C₁₋₆hydrocarbyleneC(═O)C₁₋₆-hydrocarbyleneheteroaryl,C₁₋₆hydrocarbyleneC(═O)Het, C₁₋₆-hydrocarbyleneC(═O)NR^(a)R^(b),C₁₋₆hydrocarblyneneOR^(a), C₁₋₆-hydrocarbyleneNR^(a)C(═O)R^(a),C₁₋₆hydrocarbyleneOC₁₋₆hydrocarbyleneOR^(a),C₁₋₆hydrocarbyleneNR^(a)R^(b), C₁₋₆ hydrocarbyleneC(═O)OR^(a),C₁₋₆-hydrocarbylene-O—C₁₋₆hydrocarbyleneC(═O)OR^(a), C₁₋₆hydrocarbyleneSR^(a), C₁₋₆hydrocarbyleneSO₂R^(a), andC₁₋₆hydrocarbyleneS(═O)R^(a); C₁₋₆-hydrocarbyleneSO₂NR^(a)R^(b);C₁₋₆hydrocarbyleneNSO₂R^(a);

[0095] R⁴ is selected from the group consisting of aryl, aryloxy,alkoxy, heteroaryl, halo, OH, CN, NO₂, CF₃, CF₃O, NR^(a)R^(b),N═CR^(a)R^(b), C₁₋₃-hydrocarbylene-O-aryl,C₁₋₃hydrocarbylene-O-heteroaryl, C₁₋₃-hydrocarbyleneOR^(a),

[0096] wherein A is a 5- or 6-membered ring, either saturated orpartially or fully unsaturated, containing carbon atoms and one to threeheteroatoms selected from oxygen, nitrogen, and sulfur;

[0097] or R³ and R⁴ can be taken together to form a 5-, 6-, or7-membered saturated or partially unsaturated ring;

[0098] R^(a) and R^(b), independently, are selected from the groupconsisting of hydrogen, C₁₋₆alkyl, C₃₋₈cycloalkyl, aryl, heteroaryl,arylC₁₋₃alkyl, heteroarylC₁₋₃alkyl, C₁₋₃hydrocarbylenearyl,C₁₋₃hydrocarbyleneheteroaryl, SO₂aryl, SO₂C₁₋₄-alkyl, and Het;

[0099] p=0-4; and

[0100] q=0-8;

[0101] or a pharmaceutically acceptable salt thereof;

[0102] wherein when R³ and R⁴ are aryl and/or heteroaryl, each can besubstituted with one to five groups selected from OR^(a), alkyl, aryl,aryloxy, alkoxy, halo, SR^(a), C(═O)R^(a), CN, CF₃, OCF₃,C₁₋₃hydrocarbyleneCN, C₁₋₃hydrocarbyleneOR^(a), heteroaryl (optionallysubstituted with OR^(a)), and NO₂, or the two substitutents can be takentogether to form a 3-, 4-, or 5-membered component of a 5-, 6-, or7-membered saturated or partially unsaturated ring. In other words,substituents R³ and R⁴ can be taken together with the carbon atoms towhich they are attached to form a 5-, 6-, or 7-membered saturated orpartially unsaturated ring.

[0103] Another embodiment of the present invention provides a compoundof Formula (I) wherein:

[0104] R¹ is selected from the group consisting of C₁₋₆ alkyl, andC₁₋₆hydrocarbylenearyl;

[0105] R², independently, is selected from the group consisting of C₁₋₄alkyl, and OH;

[0106] R³ is selected from the group consisting of hydrogen, alkyl,aryl, heteroaryl, C(═O)R^(a), C(═O)OR^(a), C(═O)NR^(a)R^(b),C(═O)SR^(a), C(═S)NR R^(b), SO₂R^(a), SO₂NR^(a)R^(b), S(═O)R^(a),S(═O)NR^(a)R^(b), C(═O)NR^(a)C₁₋₆hydrocarbyleneOR^(a),C(═O)NR^(a)C₁₋₆hydrocarbyleneHet, C(═O)C₁₋₆hydrocarbylenearyl,C(═O)C₁₋₆-hydrocarbyleneheteroaryl, C₁₋₆hydrocarbylenearyl,C₁₋₆-hydrocarbyleneheteroaryl, C₁₋₆hydrocarbyleneHet,C₁₋₆-hydrocarbyleneC(═O)C₁₋₆hydrocarbylenearyl,C₁₋₆hydrocarbyleneC(═O)C₁₋₆-hydrocarbyleneheteroaryl,C₁₋₆hydrocarbyleneC(═O)Het, C₁₋₆-hydrocarbyleneC(═O)NR^(a)R^(b),C₁₋₆hydrocarbyleneOR^(a), C₁₋₆-hydrocarbyleneNR^(a)C(═O)R^(a),C₁₋₆-hydrocarbyleneOC₁₋₆hydrocarbyleneOR^(a),C₁₋₆hydrocarbyleneNR^(a)R^(b), C₁₋₆hydrocarbyleneC(═O)OR^(a),C₁₋₆-hydrocarbylene-O-C₁₋₆hydrocarbyleneC(═O)OR^(a),C₁₋₆-hydrocarbyleneSR^(a), C₁₋₆hydrocarbyleneSO₂R^(a), andC₁₋₆hydrocarbyleneS(═O)R^(a); C₁₋₆-hydrocarbyleneSO₂NR^(a)R^(b);C₁₋₆hydrocarbyleneNSO₂R^(a);

[0107] R⁴ is selected from the group consisting of aryl, aryloxy,alkoxy, heteroaryl, halo, OH, CN, NO₂, CF₃, CF₃O, NR^(a)R^(b),N═CR^(a)R^(b), C₁₋₃-hydrocarbylene-O-aryl,C₁₋₃hydrocarbylene-O-heteroaryl, C₁₋₃-hydrocarbyleneOR ^(a),

[0108] wherein A is a 5- or 6-membered ring, either saturated orpartially or fully unsaturated, containing carbon atoms and one to threeheteroatoms selected from oxygen, nitrogen, and sulfur;

[0109] or R³ and R⁴ can be taken together to form a 5-, 6-, or7-membered saturated or partially unsaturated ring;

[0110] R^(a) and R^(b), independently, are selected from the groupconsisting of hydrogen, C₁₋₆alkyl, C₃₋₈cycloalkyl, aryl, heteroaryl,arylC₁₋₃alkyl, heteroarylC₁₋₃alkyl, C₁₋₃hydrocarbylenearyl,C₁₋₃hydrocarbyleneheteroaryl, SO₂aryl, SO₂C₁₋₄-alkyl, and Het;

[0111] p=0-4; and

[0112] q=0-8;

[0113] or a pharmaceutically acceptable salt thereof;

[0114] wherein when R³ and R⁴ are aryl and/or heteroaryl, each can besubstituted with one to five groups selected from OR^(a), alkyl, aryl,aryloxy, alkoxy, halo, SR^(a), C(═O)R^(a), CN, CF₃, OCF₃,C₁₋₃hydrocarbyleneCN, C₁₋₃hydrocarbyleneOR^(a), heteroaryl (optionallysubstituted with OR^(a)), and NO₂, or the two substitutents can be takentogether to form a 3-, 4-, or 5-membered component of a 5-, 6-, or7-membered saturated or partially unsaturated ring. In other words,substituents R³ and R⁴ can be taken together with the carbon atoms towhich they are attached to form a 5-, 6-, or 7-membered saturated orpartially unsaturated ring.

[0115] Compounds of Formula (I) are serotonin (5-HT) receptor ligands,and as such are useful in treating animals (including humans, farmanimals, pets, and other animals) against diseases, disorders, andconditions of the central nervous system.

[0116] In one of the preferred embodiments, R¹ is hydrogen.

[0117] In another one of the preferred embodiments, p is 0, 1, or 2.

[0118] In yet another one of the preferred embodiments p is 1, 2, or 3.

[0119] In yet another one of the preferred embodiments p is 0.

[0120] In yet another one of the preferred embodiments, q is 0-4.

[0121] In yet another one of the preferred embodiments q is 2, 3, or 4.

[0122] In yet another one of the preferred embodiments q is 1.

[0123] In yet another one of the preferred embodiments q is 0.

[0124] In yet another one of the preferred embodiments R³ is hydrogen,C₁₋₈alkyl, R⁵R⁶NC(═O)CH₂—, R⁷SC₁₋₈alkylene, or aryloxy(CH₂)₂—.

[0125] In yet another one of the preferred embodiments R³ is hydrogen.

[0126] In yet another one of the preferred embodiments R³ is C₁₋₈alkyl,R⁵R⁶NC(═O)CH₂— or aryloxy(CH₂)₂—.

[0127] In yet another one of the preferred embodiments R³ is:2-(3-methoxyphenoxy)ethyl, 2-(3-nitrophenoxy)ethyl,2-(3-isopropylphenoxy)ethyl, 2-(4-pyridyloxy)ethyl, 3-phenoxypropyl,3-(3-chlorophenoxy)propyl, 3-(4-fluorophenoxy)propyl, 2-phenoxyethyl,N-(2,3-dimethylphenyl)amino-carbonylmethyl,N-(3-methylphenyl)aminocarbonylmethyl,N-(2-fluoro-4-methylphenyl)aminocarbonylmethyl,N-mesitylaminocarbonylmethyl, N-(4-methoxyphenyl)aminocarbonylmethyl,N-(phenyl)aminocarbonylmethyl, N-(4-fluorophenyl)aminocarbonylmethyl,N-(3-nitrophenyl)aminocarbonylmethyl,N-(3-methoxyphenyl)aminocarbonylmethyl,N-(4-cyanophenyl)aminocarbonylmethyl,N-(3,5-dimethoxyphenyl)aminocarbonylmethyl,N-(2,4-dimethoxyphenyl)amino-carbonylmethyl,N-(3-chloro-4-fluorophenyl)aminocarbonylmethyl, 2-anilinoethyl,1H-benzimidazol-2-ylmethyl, isobutoxycarbonylmethyl, carboxymethyl,N,N-dimethylaminocarbonylmethyl, aminocarbonylmethyl,2-(phenylsulfinyl)ethyl, 2-(phenylsulfonyl)ethyl, 2-hydroxyethyl,2-(4-chlorophenoxy)ethyl, 2-(4-fluorophenoxy)ethyl, 2-(phenylthio)ethyl,2-aminoethyl, 2-(anilinocarbonylamino)-ethyl, 2-(benzoylamino)ethyl,2-(phenylsulfonylamino)ethyl, N-(4-methoxyphenyl)aminocarbonylethyl,N-phenylaminocarbonylmethyl, N-(2-pyridyl)aminocarbonylmethyl,N-(4-methoxyphenyl)aminocarbonylmethyl,N-(2,3-dimethylphenyl)aminocarbonylmethyl,N-(5,6,7,8-tetrahydro-1-naphthalenyl)aminocarbonylmethyl,3-ethylanilinocarbonylmethyl, 3-isopropylanilinocarbonylmethyl,N-(3-tert-butylphenyl)aminocarbonylmethyl,N-(1,3-benzothiazol-2-yl)aminocarbonylmethyl,N-(4-methyl-1,3-thiazol-2-yl)aminocarbonylmethyl,N-(5-methyl-1,3-thiazol-2-yl)aminocarbonylmethyl,N-(4-tert-butyl-1,3-thiazol-2-yl)aminocarbonylmethyl,N-(4-phenyl-1,3-thiazol-2-yl)aminocarbonylmethyl, 3-phenylpropyl,2-phenoxyethyl, 2-(4-chlorophenoxy)ethyl, 2-(4-fluorophenoxy)ethyl,2-(5,7-dibromo-8-quinolinyloxy)ethyl, 2-(8-quinolinyloxy)ethyl,2-(5-isoquinolinyloxy)ethyl, 2-(5-quinolinyloxy)ethyl,2-(5,6,7,8-tetrahydro-1-naphthalenyloxy)ethyl,2-(1,3-benzodioxol-5-yloxy)ethyl, 2-(1H-indol-4-yloxy)ethyl,2-(5,6,7,8-tetrahydro-2-naphthalenyloxy)ethyl, 2-(7-quinolinyloxy)ethyl,2-[(5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-1-yl)oxy]ethyl,N-(3-chloro-2-methylphenyl)aminocarbonylmethyl,N-[2-methyl-3-(trifluoromethyl)phenyl]aminocarbonylmethyl,N-(5,6,7,8-tetrahydronaphthalen-1-yl)aminocarbonylmethyl,N-(4-methyl-1,3-thiazol-2-yl)aminocarbonylmethyl,N-(1,3-dihydro-2-benzofuran-4-yl)aminocarbonylmethyl,N-(4-methoxyphenyl)aminocarbonylmethyl,N-(3-pyridyl)aminocarbonylmethyl,N-(4-methyl-1,3-thiazol-2-yl)aminocarbonylmethyl, or2-(5,6,7,8-tetrahydronaphthalen-1-yloxy)ethyl.

[0128] In yet another one of the preferred embodiments R⁴ is phenyl,optionally substituted at the 2-position of the phenyl.

[0129] In yet another one of the preferred embodiments R⁴ is2-ethoxyphenyl, 2-(C₃₋₈cycloalkyloxy)phenyl, or 2-chlorophenyl.

[0130] In yet another one of the preferred embodiments R⁴ is aryl,substituted at the 10-position of formula (I).

[0131] In yet another one of the preferred embodiments R⁴ is:5-pyrimidinyl, 3,4-dimethoxyphenyl, 3,5-difluorophenyl,4-n-butyloxyphenyl, 4-trifluoromethoxyphenyl, 3,4-dichlorophenyl,2-naphthyl, 4-pyridinyl, bromo, benzhydrilideneamino, amino,N-(phenylsulfonyl)amino, phenoxy, 3-(phenoxy)propyl,3-(2-naphthyloxy)propyl, 3-(1-naphthyloxy)propyl,3-([1,1′-biphenyl]-4-yloxy)propyl, 3-(3-methoxyphonoxy)propyl,3-(4-methoxyphenoxy)propyl, 3-(4-chlorophenoxy)propyl,3-(3-chlorophenoxy)propyl, 3-(2-chlorophenoxy)propyl,3-(2,4-dichlorophenoxy)propyl, 3-(2,5-dichlorophenoxy)propyl,3-(4-fluorophenoxy)propyl, 3-(4-methylphenoxy)propyl,3-(4-cyanophenoxy)propyl, 3-(pyridin-2-yloxy)propyl,3-(2-bromophenoxy)propyl, 3-(2-iodophenoxy)propyl,3-(2-ethylphenoxy)propyl, 3-(2-isopropylphenoxy)propyl,3-(2-cyanophenoxy)propyl, 3-(pyridin-3yloxy)propyl,3-(3-fluorophenoxy)propyl, 3-(3-bromophenoxy)propyl,3-(3-iodophenoxy)propyl, 3-(3-isopropylphenoxy)propyl,3-[3-(trifluoromethyl)phenoxy]propyl,3-[3-(trifluoromethoxy)phenoxy]propyl, 3-(3-ethylphenoxy)propyl,3-(3-tert-butylphenoxy)propyl, 3-(pyridin-4yloxy)propyl,3-(4-methoxyphenoxy)propyl, 3-[4-(benzyloxy)phenoxy]propyl,3-(4-bromophenoxy)propyl, 3-(4-iodophenoxy)propyl,3-(4-ethylphenoxy)propyl, 3-(4-tert-butylphenoxy)propyl,3-[4′-(bromo[1,1′-biphenyl]-4-yl)oxy]propyl,3-(2,3-difluorophenoxy)propyl, 3-(2,4-dibromophenoxy)propyl,3-(2,4-difluorophenoxy)propyl, 3-(2-methoxy-4-methylphenoxy)propyl,3-(4-iodo-2-methylphenoxy)propyl, 3-(2,5-difluorophenoxy)propyl,3-(2-chloro-5-methylphenoxy)propyl,3-(2-isopropyl-5-methylphenoxy)propyl, 3-(2,6-difluorophenoxy)propyl,3-(2,6-dichlorophenoxy)propyl, 3-(2,6-dimethylphenoxy)propyl,3-(2-fluoro-6-methylphenoxy)propyl, 3-hydroxypropyl,3-(2,3,6-trimethylphenoxy)propyl, 3-(mesityloxy)propyl,3-(2,6-dibromo-4-fluorophenoxy)propyl,3-(4-chloro-3-fluorophenoxy)propyl, 3-(4-chloro-3-methylphenoxy)propyl,3-(3-chloro4-fluorophenoxy)propyl, 3-(1,3-benzodioxol-5-yloxy)propyl,3-(3,5-dichlorophenoxy)propyl, 3-(3,5-dimethylphenoxy)propyl,3-(3,5-dimethoxyphenoxy)propyl,3-(5,6,7,8-tetrahydro-1-naphthalenyloxy)propyl,3-[(2,4-dichloro-1-naphthyl)oxy]propyl,3-[4-methoxy-1-naphthyl)oxy]propyl, 3-[4-chloro-1-naphthyl)oxy]propyl,3-[1,6-dibromo-2-naphthyl)oxy]propyl, 3-[1-bromo-2-naphthyl)oxy]propyl,3-(2,3,4,5,6-pentafluorophenoxy)propyl, 3-(5-isoquinolinyloxy)propyl,2-methyl-4-methoxyphenyl, 2-ethoxyphenyl, phenyl, phenoxy, 4-pyridinyl,4-methoxyphenyl, 3,5-difluorophenyl, 3-[1,1′-biphenyl]-2-yloxypropyl,chloro, 2,6-difluorophenyl, bromo, 2-methylphenyl, 2-methoxyphenyl,2-propoxyphenyl, 2-fluorophenyl, 2,4-dichlorophenyl,3-(2,4-dibromophenoxy)propyl, 3-(5-chloro-8-quinolinyloxy)propyl,fluoro, 2,6-difluorophenyl, 4-methoxy-2-methylphenyl, or2,4-dichlorophenyl.

[0132] In yet another one of the preferred embodiments R⁴ is10-(2-ethoxyphenyl).

[0133] In still another embodiment, R⁴ is an optionally substitutedbicyclic ring system

[0134] wherein the bicyclic ring can represent, for example,benzoxazole, benzothiazole, benzisoxazole, benzimidazole, quinoline,indole, benzothiophene, or benzofuran.

[0135] In still another embodiment, R⁴ is an optionally substitutedbicyclic ring system,

[0136] wherein t is an integer 1 or 2, and each X, independently isC(R^(a))₂, O, S, or NR^(a). The bicyclic ring comprising the R⁴subsituent typically is attached to the rest of the molecule by a phenylring carbon atom.

[0137] In another embodiment R⁴ is represented by an optionallysubstituted bicyclic ring

[0138] wherein t is 1 or 2, and X, independently, CH₂ or O. Especiallypreferred substituents include:

[0139] Within this particular group of compounds, nonlimiting examplesof substituents for the bicyclic ring include halogen (e.g., chlorine),C₁₋₃alkyl (e.g., methyl, ethyl, or isopropyl), OR^(a), (e.g., methoxy,ethoxy, or hydroxy), CO₂R^(a), halomethyl or halomethoxy (e.g.,trifuoromethyl or trifluoromethyoxy), cyano, nitro, and N(R^(a))₂.

[0140] Another particularly preferred compound of the invention is acompound of formula (I), which is a compound of Formula (II):

[0141] wherein p is 0, 1, 2, or 3; and R², R³, R⁴, Ar, and q are asdefined above with respect to Formula (I).

[0142] Another particularly preferred compound of the invention is acompound of formula (I), which is a compound of Formula (III):

[0143] wherein R² and q are as defined above with respect to Formula(I); R⁸ is H or C₁₋₆alkyl, R⁹ is H, C₁₋₆alkyl, C₁₋₆alkyl S—, or halo,and R¹⁰ is C₁₋₆alkyl or C₃₋₈cycloalkyl.

[0144] More specific diseases, disorders, and/or conditions for whichcompounds of Formula (I) may have activity include, but are not limitedto, obesity, depression, schizophrenia, schizophreniform disorder,schizoaffective disorder, delusional disorder, a stress related disease(e.g., general anxiety disorder), panic disorder, a phobia, obsessivecompulsive disorder, post-traumatic-stress syndrome, immune systemdepression, a stress induced problem with the urinary, gastrointestinalor cardiovascular system (e.g., stress incontinence), neurodegenerativedisorders, autism, chemotherapy-induced vomiting, hypertension, migraineheadaches, cluster headaches, sexual dysfunction in a mammal (e.g., ahuman), addictive disorder and withdrawal syndrome, an adjustmentdisorder, an age-associated learning and mental disorder, anorexianervosa, apathy, an attention-deficit disorder due to general medicalconditions, attention-deficit hyperactivity disorder, behavioraldisturbance (including agitation in conditions associated withdiminished cognition, e.g., dementia, mental retardation or delirium),bipolar disorder, bulimia nervosa, chronic fatigue syndrome, conductdisorder, cyclothymic disorder, dysthymic disorder, fibromyalgia andother somatoform disorders, generalized anxiety disorder, an inhalationdisorder, an intoxication disorder, movement disorder (e.g.,Huntington's disease or Tardive Dyskinesia), oppositional defiantdisorder, peripheral neuropathy, post-traumatic stress disorder,premenstrual dysphoric disorder, a psychotic disorder (brief and longduration disorders and psychotic disorder due to medical condition),mood disorder (major depressive or bipolar disorder with psychoticfeatures) seasonal affective disorder, a sleep disorder, a specificdevelopmental disorder, agitation disorder, selective serotonin reuptakeinhibition (SSRI) “poop out” syndrome or a Tic disorder (e.g.,Tourette's syndrome).

[0145] Preferred diseases, disorders, and/or conditions for whichcompounds of Formula (I) have activity include anxiety, depression,schizophrenia, epilepsy, migraine, Alzheimers disease, sleep disorders,obesity, a stress related disease, and withdrawal from drug abuse.

[0146] More preferred diseases, disorders, and/or conditions for whichcompounds of Formula (I) have activity include anxiety, depression,epilepsy, migraine, obesity, a stress related disease, and withdrawalfrom drug abuse.

[0147] FIGS. 1-26 illustrate the preparation of intermediate indolecompounds of Formula (IV):

[0148] that can be used to prepare indoline compounds of the invention.

[0149] The compounds of the invention can be prepared as illustrated inFIGS. 27-32, using synthetic methods similar to those described herein,or using synthetic methods known in the art.

[0150] Intermediate (7, 8, 9, or 10-) arylazepinoindoles (Formula (IV)wherein R⁴=Ar), can be prepared by the reactions depicted in FIG. 1. Asshown in FIG. 1, a (7, 8, 9, or 10-) bromoazepinoindole (1) is coupledwith an arylboronic acid under Suzuki reaction conditions to afford anarylated azepinoindole (2). The final product (4) is generated either bydirect basic hydrolysis of compound (2), or by hydrogenation of benzylcompound (3), which are obtained from compound (2) by reduction with asuitable reducing agent such as lithium aluminum hydride (LAH orLiAlH₄).

[0151] Intermediate 10-arylazepinoindole compounds of Formula (IV) canbe prepared by the reactions depicted in FIG. 2. As shown in FIG. 2, thebenzoyl group of compound (1) is removed under basic conditions and aBoc group is introduced to afford compound (5). Coupling withbis(pinacolato)diboron under palladium catalysis gives the boroncompound (6), which is used for the synthesis. A mixture of boroncompound (6), an aryl bromide, palladium catalyst (e.g., Pd₂(dba)₃), anda base (e.g., Cs₂CO₃) in methanol and dioxane is shaken for about 48hours at about 90° C. to generate compound (7). The mixtures are cooledovernight, treated with acidic resin at about 65° C., and then washedsuccessively with suitable solvents such as water, methanol,tetrahydrofuran, methylene chloride, and mixtures thereof. The resin istreated with ammonia and filtered. The filtrate is taken up to thevacuum and dried. The residue can be treated with a suitable acidsolution, such as methanol/HCl solution, to give the salt form and/orpurified by HPLC to yield the final product, a 10-arylazepinoindole (8).

[0152] Intermediate indole compounds of formula (IV) (whereinR⁴=ArSO₂NH) can be prepared by the reaction scheme depicted in FIG. 3.Compound (1) is reduced with a suitable reducing agent such as LAH oraluminum chloride to yield a benzyl compound (9). Under Buchwald/Hartwigamination conditions, compound (9) is reacted with benzophenone imine toafford compound (10), which is treated with a suitable acid solution,such as THF/HCl solution, to generate the 10-aminoazepinoindole (11).Subsequent sulphonylation and reduction, e.g., hydrogenation, yields thefinal product (13).

[0153] Intermediate compounds of Formula (IV) (wherein R⁴=ArO) can beprepared by the reaction scheme depicted in FIG. 4. The aryloxy group isintroduced on the indole ring by treating compound (1) with asubstituted phenol in the presence of copper (I) oxide and cesiumcarbonate to generate compound (14). Reduction with a reducing agent,such as lithium aluminum hydride and hydrogenation yields the finalproduct (16).

[0154] Intermediate compounds of Formula (IV) (whereinR⁴=ArO(CH₂)_(n)CH₂) can be prepared by the reaction scheme depicted inFIG. 5. Sonogashira coupling of the aryl bromide (1) with propargylalcohol, in pyrrolidine, using a suitable catalyst such astetrakistriphenylphosphine palladium (0) and copper (1) iodide affordsthe aryl alkyne (17). Exhaustive hydrogenation of the alkyne leads tothe alkane (18). Using standard Mitsunobu reaction conditions, variousphenols are reacted to provide the corresponding aryl ethers (19).Removal of the benzamide functionality is accomplished through basichydrolysis to give the final products (20) which can be trapped as theirhydrochloride salts.

[0155] Intermediate compounds of Formula (IV) (wherein R³=ArO(CH₂)_(n))can be prepared by the reaction scheme depicted in FIG. 6 (whereinn=1-3). Protection of 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (21) asthe tert-butyl carbamate (22), followed by alkylation with a suitablealkylating agent, such as a haloester, leads to the protected ester(23). Reduction of the ester (23) affords the primary alcohol (24).Standard Mitsunobu reaction conditions leads to the aryl ether (25),which is deprotected and isolated as the appropriate salt of compound(26) using suitable acids.

[0156] Intermediate compounds of Formula (IV) (wherein R³=ArO(CH₂)_(n))also can be prepared by the reaction scheme depicted in FIG. 7 (where nis 2 or 3). The tert-butyl carbamate protected azepinoindole (22) isalkylated with a suitable alkylating agent, such as bromochloropropane.Displacement with a substituted phenol affords compound (25), which thencan be deprotected with acid to yield (28) as appropriate salts.

[0157] Intermediate compounds of Formula (IV) (wherein R³=ArO(CH₂)_(n),R⁴=Br, H) also can be prepared by the reaction scheme depicted in FIG. 8(where n is 2 or 3). The tert-butyl carbamate protected10-bromoazepinoindole (5) is alkylated with a suitable alkylating agentsuch as phenoxybromoalkane. Deprotection with acid affords compound (30)as appropriate salts. Hydrogenolysis of (29) generates the dehalogenatedcompound (25), which is deprotected with acid to generate (28) asappropriate salts.

[0158] Intermediate compounds of Formula (IV) (whereinR³=(CH₂)_(n)CONHAr) can be prepared by the reaction scheme depicted inFIG. 9. The ester (23) is hydrolyzed, for example, with 1N NaOH inmethanol, and the resulting acid (31) is condensed with a suitableaniline using coupling conditions such as diisopropylcarbodiimde anddimethylaminopyridine (DMAP) in THF or EEDQ in THF or EtOH, to yieldamide (32). The Boc protecting group is cleaved from the amide using asuitable acid solution, such as TFA in CH₂Cl₂, and the crude product canbe treated with HCl in ether to yield the hydrochloride salt of (33).

[0159] Intermediate compounds of Formula (IV) (wherein R³=(CH₂)_(n)NHAr)can be prepared by the reaction scheme depicted in FIG. 10. Amide (32)is reduced with a suitable reducing agent, such as LAH in THF, to yieldthe corresponding secondary amine (34), which is in turn deprotectedwith an acid like TFA in CH₂Cl₂, to yield diamine (35).

[0160] Intermediate compounds of Formula (IV) (whereinR³=(CH₂)_(n)benzimidazole) can be prepared by the reaction schemedepicted in FIG. 11. Acid (31) is condensed with a substitutedo-phenylenediamines using isobutyl chloroformate, triethylamine, andacetic acid in THF. Benzimidazole (36) is deprotected with a suitableacid solution, such as TFA in CH₂Cl₂, and the crude product may beconverted to the hydrochloride salt of (37) using a suitable acidsolution, such as HCl in ethyl ether.

[0161] Intermediate compounds of Formula (IV) (whereinR³=(CH₂)_(n)COOR^(a)) can be prepared by the reaction scheme depicted inFIG. 12. The acid (31) is condensed with an alcohol and the resultingester (38) is deprotected using a suitable acid solution, such as TFA inCH₂Cl₂, to yield the amino ester (39).

[0162] Intermediate compounds of Formula (IV) (wherein R³=(CH₂)_(n)COOH)can be prepared by the reaction scheme depicted in FIG. 13. The acid(31) is treated with a suitable acid solution, such as TFA in CH₂Cl₂,and the crude product may be combined with a suitable acid solution,such as HCl in ethyl ether, to yield hydrochloride salt of (40).

[0163] Intermediate compounds of Formula (IV) (whereinR³=(CH₂)_(n)CONR^(a)R^(b)) can be prepared by the reaction schemedepicted in FIG. 14. N-Boc azepinoindole (22) is alkylated with anN-substituted haloacetamide (e.g., iodoacetamide or2-chloro-N,N-dimethylacetamide) using NaH in DMF. The resultingsubstituted azepinoindoles is deprotected with a suitable acid solution,such as TFA in CH₂Cl₂, and the crude product may be treated with asuitable acid solution, such as HCl in ethyl ether, to form thehydrochloride salt of (42).

[0164] Intermediate compounds of Formula (IV) (whereinR³=(CH₂)_(n)SO₂Ar) can be prepared by the reaction scheme depicted inFIG. 15. N-Boc azepinoindole (22) is alkylated with a suitablealkylating agent such as chloroalkyl phenyl sulfone or chloroalkylphenyl sulfoxide, in the presence of either a suitable basic solution,such as NaH in DMF, or under phase transfer conditions (e.g., Bu₄NHSO₄,KOH, H₂O, CH₂Cl₂) to yield an alkylated azepinoindole (43). The Bocprotecting group is removed by treating the alkylated azepinoindole (43)with a suitable acid solution such as TFA in CH₂Cl₂, to yield freeamines (44).

[0165] Intermediate compounds of Formula (IV) (wherein R³=(CH₂)_(n)SAr)can be prepared by the reaction scheme depicted in FIG. 16. Alcohol (24)is treated with a suitable leaving group-containing compound such asmethanesulfonyl chloride, in the presence of a suitable basic solution,such as triethylamine in CH₂Cl₂, to yield a mesylate (45). The mesylate(45) is treated with thiophenol, under phase transfer conditions (e.g.,Bu₄NHSO₄, NaOH, H₂O, CH₂Cl₂) to yield a phenyl thioether (46). Thephenyl thioether (46) is treated with a suitable acid solution, such asTFA in CH₂Cl₂, to remove the Boc protecting group to give (47).

[0166] Intermediate compounds of Formula (IV) (wherein R³=(CH₂)_(n)NH₂)can be prepared by the reaction scheme depicted in FIG. 17. The mesylate(45) is treated with a suitable azide such as sodium azide in DMF, toyield an azide (48). This azide is reduced by catalytic hydrogenolysis(e.g., H₂, 10% Pd/C, ethyl acetate, ethanol) to yield an amine (49). Theamine (49) is treated with a suitable acid solution, such as TFA inCH₂Cl₂, and the resulting crude diamine can be treated with a suitableacid solution, such as HCl in ethyl ether, to yield the dihydrochloridesalt of (50).

[0167] Intermediate compounds of Formula (IV) (whereinR³=(CH₂)_(n)NHCONHAr) can be prepared by the reaction scheme depicted inFIG. 18. The amine (49) is treated with aryl isocyanate in CH₂Cl₂ toyield urea (51). The urea (51) is treated with a suitable acid solution,such as TFA in CH₂Cl₂, and the resulting crude amine ccan be treatedwith a suitable acid solution, such as HCl in ethyl ether, to yieldhydrochloride salt of (52).

[0168] Intermediate compounds of Formula (IV) (whereinR³=(CH₂)_(n)NHCOAr) can be prepared by the reaction scheme depicted inFIG. 19. The amine (49) is treated with a suitable aroyl chloride, inthe presence of a suitable basic solution, such as diisopropylethylaminein CH₂Cl₂, to yield an amide (53). The amide (53) is treated with asuitable acid solution, such as TFA in CH₂Cl₂, and the resulting crudeamine may be treated with a suitable acid solution, such as HCl in ethylether, to yield hydrochloride salt of (54).

[0169] Intermediate compounds of Formula (IV) (whereinR³=(CH₂)_(n)NHSO₂Ar) can be prepared by the reaction scheme depicted inFIG. 20. The amine (49) is treated with a suitable arylsulfonylchloride, in the presence of a suitable basic solution, such asdiisopropylethylamine in CH₂Cl₂, to yield sulfonamide (55). Thesulfonamide (55) is treated with a suitable acid solution, such as TFAin CH₂Cl₂, and the resulting crude amine may be treated with a suitableacid solution, such as HCl in ethyl ether, to yield hydrochloride saltof (56).

[0170] Intermediate compounds of Formula (IV) (wherein R²=5,5-di-Me) canbe prepared by the reaction scheme depicted in FIG. 21. Thephthalimido-protected tryptamine (57) is reverse prenylated, using theprocedures described by Depew et al. (J. Am. Chem. Soc. 1996, 118,12463) and Schkeryantz et al. (J. Am. Chem. Soc. 1999, 121, 11964), toprovide (58). Standard deprotection of (58) (e.g., NH₂NH₂, EtOH)provides (59). The amine group of (59) is re-protected (e.g., CbzCl) toprovide (60). Oxidation of the vinyl group of (60) (e.g., OsO₄, NMO)provides diol (61), that is oxidatively cleaved (e.g., NaIO₄) toaldehyde (62). Mild catalytic hydrogenation of (62) accomplishes Cbzdeprotection, that is followed by in situ intramolecular cyclization tothe imine and imine reduction, to provide an amine (63), which may beformulated as the hydrochloride salt.

[0171] Intermediate compounds of Formula (IV) can be prepared by thereaction scheme depicted in FIG. 22. Acylation of 4-chloroindole (64)(oxalyl chloride, followed by an EtOH quench) provides an ethyl4-chloroindole glyoxalate (65), which is reduced (e.g., LiAlH₄) to the4-chloroindole-3-ethanol (66). Substitution of the alcohol (66) isachieved using a suitable azide, such as Zn(N₃)₂, under Mitsunobureaction conditions to provide (67). Malonate addition to (67) isaccomplished as described by Kuehne J. Org. Chem., 63, 9427 (1998), toprovide a malonyl enolate (68). Alkylation of the malonyl enolate (68)with a suitable alkylating agent such as NaOMe and MeI, provides (69).The azide group of (69) is reduced (sequential addition of PMe₃ and H₂O)to provide an aminoester (70). The aminoester (70) undergoesintramolecular cyclization, providing lactam (71) upon reflux as asolution in MeOH. Racemate (71) is separated into the enantiomers (72)and (73) by chiral support chromatography. The assignment of theabsolute configurations to (72) and (73) is made by x-raycrystallographic analysis. The lactam group of each enantiomer isseparately reduced (BH₃) to provide amines (74) (from reduction of (72))and (75) (from reduction of (73)), which may be formulated as thefumarate salts.

[0172] Intermediate compounds of Formula (IV) (wherein R⁴=7-F) can beprepared by the reaction scheme depicted in FIG. 23. Beginning with6-fluoroindole (76), the preparation of intermediates (77), (78), (79),and (80) follows the methods described respectively for (65), (66),(67), and (68) (FIG. 22). The azido group of (80) is reduced bycatalytic hydrogenation, and the resulting aminoester is subjected(without isolation) to thermal cyclization to provide (81). Reduction(e.g., BH₃) of the lactam of (81) provides an amine (82), which may beformulated as the fumarate salt.

[0173] Intermediate compounds of Formula (IV) (R⁴=7-F) can be preparedby the reaction scheme depicted in FIG. 24. According to the reactionsequence of FIG. 23, alkylation of the malonyl enolate of (80), asdescribed previously for the preparation of (69), provides (83).Racemate (83) is separated into the enantiomers (84) and (85) by chiralsupport chromatography. The assignment of the absolute configurations to(84) and (85) is made by correlation of their CD spectra to those of(72) and (73). The lactam group of each enantiomer is separately reducedwith a suitable reducing agent such as BH₃, to provide amines (86) (fromreduction of (84)) and (87) (from reduction of (85)), which may beformulated as the fumarate salts.

[0174] As shown in FIG. 25, compounds of Formula (IV) may also beprepared starting with the corresponding nitrobenzenes (96), benzoicacids (97) or anilines (98), many of which are commercially available orknown in the scientific literature, or can be prepared by generalprocedures known to those skilled in the art (for examples, see Larock,R. C., Comprehensive Organic Transformations, 2^(nd) edition, 1999,Wiley-VCH Publishers, New York). For example, reduction of the nitrogroup using a variety of conditions or reagents such as SnCl₂ in acid,LAH, sodium borohydride, hydrazine, or hydrogen in the presence ofappropriate catalysts such as palladium, platinum, nickel, etc (seeHudlicky, M. “Reductions in Organic Chemistry”, 1984, Ellis Horwood,Ltd., Chichester, UK) gives the corresponding anilines (98).Alternatively, benzoic acids (97) can be converted to the correspondinganilines (98) via reactions known to those in the art, such as theCurtius reaction, (for examples, see Larock, R. C., ComprehensiveOrganic Transformations, 2^(nd) edition, 1999, Wiley-VCH Publishers, NewYork, 868-869). Conversion of these anilines to the correspondingphenylhydrazines (99) can be accomplished through the-well-knownnitrosation/reduction sequence (e.g., treatment of (98) with NaNO₂ underacidic conditions, such as HOAc, followed by reduction of the resultingN-nitrosoamine with agents such as lithium aluminum hydride or zinc andan organic acid such as acetic or trifluoracetic acid). Reaction of (99)with ketones, such as 1-benzoylazepan-4-one, under Fisher-indolecyclization conditions as described, for example, in “Indoles, BestSynthetic Methods” (Academic Press, 1999, San Diego, Calif.) producesazepinoindoles (100). These compounds can be treated as described aboveto give azepinoindoles (88) and (89).

[0175] Intermediate (7, 8, 9, or 10-) aminoazepinoindoles (Formula (IV)wherein R⁴=NR^(a)R^(b)), can be prepared by the reactions depicted inFIG. 26. As shown in FIG. 26, a (7, 8, 9, or 10-) bromoazepinoindole(116) is coupled with an amine via palladium catalysis (for example, seeBuchwald et al, J. Org. Chem. 2000, 65, 1158-1174). When R³=H, the finalproduct (119) can then be generated by deprotection of compound (117)using the methods found in Green, T. W.; Wuts, P. G. M. ProtectiveGroups in Organic Synthesis, 3^(rd) edition, 1999, John Wiley & Sons,Inc., New York. Alternatively, an R³ group can be installed using themethods described above to give compound (118), which is thendeprotected.

[0176] Compounds of Formula (I) can be prepared by the reaction schemedepicted in FIG. 27. Azepinoindoles (88) are known in the literature forR³=H (See J. Med. Chem., 1968, 11, 101-106) or can be prepared asdescribed herein. When R¹ is benzoyl, amines (89) can be obtained frombasic hydrolysis (e.g., potassium hydroxide in ethylene glycol).Alternatively, when R¹ is Boc, amines (89) can be obtained under acidicconditions such as TFA in CH₂Cl₂. Reduction of (89) under conditionssuch as sodium cyanoborohydride (or sodium triacetoxyborohydride) inacidic solvents such as trifluoroacetic acid gives cis-azepinoindolines(90). Separation of cis-enantiomers (91) and (92) is carried out throughresolution techniques know in the art, such as chromatographicresolution using a chiral stationary phase (normal or reverse phase) orusing a traditional fractional crystallization of diastereomeric saltsderived using readily-available chiral acids such as (d)- or(I)-tartaric acid or their derivatives (see for example Kinbara, et al,J. Chem. Soc., Perkin Trans., 2, 1996, 2615 and Tomori, et al Bull.Chem. Soc. Jpn., 1996, 3581). Reduction of (89) under conditions such astreatment with borane-tetrahydrofuran complex followed by water andtrifluoroacetic acid (see for example Tetrahedron Letters, 1982, 23,1983-1984) gives trans-azepinoindolines (90). Resolution oftrans-enantiomers (93) and (94) is carried out as described above forthe cis-isomers.

[0177] Compounds of Formula (I) also can be prepared by the reactionscheme depicted in FIG. 28. Reduction of the azepinoindoles (88) withsuitable reducing agents, such as sodium cyanoborohydride in TFA/MeOH,yields a separable mixture of cis-and trans-azepinoindolines (95). WhenR¹ is benzoyl, deprotected azepinoindolines (90) can be obtained frombasic hydrolysis (e.g., potassium hydroxide in ethylene glycol).Alternatively, when R¹ is Boc, deprotected azepinoindolines (90) can beobtained under acidic conditions such as TFA in CH₂Cl₂. If desired,resolution of (90) or (95) may be carried out as described above.

[0178]FIG. 29 shows yet another method for obtaining compounds ofFormula (I). Bromoazepinoindoles (101) are competent partners fortransition metal catalyzed coupling reactions with aryl boronic acids togive azepinoindoles (102) (for examples of the Suzuki reaction; seeMiyaura, N., et al, Chem. Rev., 1995, 2457 and referenced therein).Typically, the Suzuki reaction is carried out using a palladium catalyst(such as Pd(PPh₃)₄, Pd(PPh₃)₂Cl₂, Pd(OAc)₂, Pd₂(dba)₃, etc), a suitableligand (such as PPh₃, Pt-Bu₃, Pcy₃, etc), a base (such as Na₂CO₃,Cs₂CO₃, amines, etc) in a solvent such as DMF, toluene, dioxane, or thelike. Removal of the R¹ protecting group by the methods described abovegives amines (103). Reduction of (103) with suitable reducing agents,such as sodium cyanoborohydride in TFA/MeOH, yields azepinoindolines(104). Further elaboration of (104), such as chloronation using NCS (forexamples, see Larock, R. C., Comprehensive Organic Transformations,2^(nd) edition, 1999, Wiley-VCH Publishers, New York), can be done togive more highly substituted azepinoindolines (105).

[0179] Compounds of Formula (I) can also be prepared as shown in FIG.30. Bromoazepinoindolines (106) where R¹ is benzoyl are deprotected viabasic hydrolysis (e.g., potassium hydroxide in ethylene glycol) to giveamines (107). The reduction of (107) is accomplished with suitablereducing agents as described above to give azepinoindolines (108) whichcan then be protected to give (109) using, for example, excessdi-tert-butyl dicarboxylate in THF/aqueous base (such as sodiumhydroxide or potassium carbonate). Subjection of (109) to Suzukireaction conditions as described above leads to azepinoindolines (110),which are deprotected to give amines (111). When R¹ is Boc, thedeprotection can be accomplished via acidic conditions such asTFA/CH₂Cl₂ or treatment with acidic resin (for example, Dowex® 50WX2-400ion-exchange resin).

[0180] Compounds of Formula (I) can also be prepared following thesequence in FIG. 31. Azepinoindoles (112) are alkylated (for example,NaH and β-bromophenetole in DMF) to give 6-substituted azepinoindoles(113). These compounds are deprotected using the methods described aboveto give amines (114). Reduction of (114) with suitable reducing agentsas described above leads to azepinoindolines (115).

[0181] Compounds of Formula (1) can also be prepared as shown in FIG.32. Ester-containing azepinoindole (39) is reduced to azepinoindoline(120) using suitable agents, such as sodium cyanoborohydride inTFA/MeOH. The protecting group R¹ is introduced to give compound (121)using standard conditions (such as those described in Green, T. W.;Wuts, P. G. M. Protective Groups in Organic Synthesis, 3^(rd) edition,1999, John Wiley & Sons, Inc., New York). The ester is hydrolyzed to theacid (122) using basic conditions such as KOH in THF/H₂O. Amide (123) isprepared from acid (122) and an amine under coupling conditions such asEEDQ in THF or a carbodiimide with base in THF. Finally, removal of R¹(using the methods such as those found in Green, T. W.; Wuts, P. G. M.Protective Groups in Organic Synthesis, 3^(rd) edition, 1999, John Wiley& Sons, Inc., New York) gives amide-containing azepinoindoline (124).

[0182] The phrases “pharmaceutically acceptable salts” or “apharmaceutically acceptable salt thereof” refer to salts prepared frompharmaceutically acceptable acids or bases, including organic andinorganic acids and bases. Salts can be prepared from pharmaceuticallyacceptable acids. Pharmaceutically acceptable salts can be obtainedusing standard procedures known by those skilled in the art, for exampleby reacting a sufficiently basic compound, such as an amine, with asuitable acid affording a physiologically acceptable anion. Suitablepharmaceutically acceptable acids include acetic, benzenesulfonic(besylate), benzoic, p-bromophenylsulfonic, camphorsulfonic, carbonic,citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic,hydrochloric, hydroiodic, isethionic, lactic, maleic, malic, mandelic,methanesulfonic (mesylate), mucic, nitric, oxalic, pamoic, pantothenic,phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic, and thelike. Examples of such pharmaceutically acceptable salts, thus, include,but are not limited to, acetate, benzoate, β-hydroxybutyrate, bisulfate,bisulfite, bromide, butyne-1,4-dioate, carpoate, chloride,chlorobenzoate, citrate, dihydrogenphosphate, dinitrobenzoate, fumarate,glycollate, heptanoate, hexyne-1,6-dioate, hydroxybenzoate, iodide,lactate, maleate, malonate, mandelate, metaphosphate, methanesulfonate,methoxybenzoate, methylbenzoate, monohydrogenphosphate,naphthalene-1-sulfonate, naphthalene-2-sulfonate, oxalate,phenylbutyrate, phenylproionate, phosphate, phthalate, phylacetate,propanesulfonate, propiolate, propionate, pyrophosphate, pyrosulfate,sebacate, suberate, succinate, sulfate, sulfite, sulfonate, tartrate,xylene sulfonate, and the like. The compounds of the Formula (I) alsocan provide pharmaceutically acceptable metal salts, in particularalkali metal (e.g., sodium, potassium, magnesium, or lithium) salts andalkaline earth metal (e.g., calcium) salts, with bases.

[0183] Compounds of Formula (I) are useful in treating diseases,disorders, and conditions of the central nervous system occurring inmammals. Typically, the mammal is a human being, but the compounds canbe used to treat other animals such as livestock, pets, or otheranimals.

[0184] It is to be understood that “a compound of Formula (I),” or apharmaceutically acceptable (acidic or basic) salt or solvate (i.e.,hydrate) thereof, can be administered as the neat compound, or as apharmaceutical composition containing the compound in combination with asuitable excipient. Such pharmaceutical compositions can be prepared bymethods and contain excipients which are known by those skilled in theart. A generally recognized compendium of such methods and ingredientsis Remington's Pharmaceutical Sciences by E. W. Martin (Mark Publ. Co.,15th Ed., 1975), the disclosure of which is incorporated herein byreference. In cases where a compound is sufficiently basic or acidic toform a stable pharmaceutically acceptable salt, administration of thecompounds as a salt may be preferred.

[0185] The compounds of this invention can be administered in oral unitdosage forms, such as aerosol sprays, buccal tablets, capsules, elixirs,pills, sachets, suspensions, syrups, tablets, troches, wafers, and thelike. The compounds also can be administered parenterally, (e.g.,subcutaneously, intravenously, intramuscularly, or by intraperitonealinjection), using forms known in the pharmaceutical art. The compoundsfurther can be administered rectally or vaginally, in such forms assuppositories or bougies, transdermally, such as with a “patch”containing active ingredient, or nasally (i.e., by inhalation).

[0186] In general, the preferred route of administration of a presentcompound is oral. For oral administration, the active compound can becombined with one or more excipients and used in the form of ingestibleaerosol sprays, buccal tablets, capsules, elixirs, pills, sachets,suspensions, syrups, tablets, troches, wafers, and the like. Suchcompositions and preparations typically contain at least 0.1% of activecompound. The percentage of the compounds in these preparations can bevaried, e.g., about 0.01 to about 60% of the weight of a given unitdosage form. The amount of active compound in such orally administeredcompositions is sufficient to provide an effective dosage level.

[0187] The aerosol sprays, buccal tablets, capsules, elixirs, pills,sachets, suspensions, syrups, tablets, troches, wafers, and the likealso can contain one or more binders, diluents disintegrating agents,excipients, lubricants, sweetening agents, or flavoring agents. Suitablebinders include, for example, gum arabic, tragacanth, acacia,polyvinylpyrrolidone, corn starch, methylcellulose, or gelatin. Suitablediluents include, for example, lactose, dextrose, sucrose, mannitol,sorbitol, and cellulose. Suitable disintegrating agents include, forexample, starches, alginic acid, and alginates. Suitable excipientsinclude dicalcium phosphate. Suitable lubricants include, for example,silica, talc, stearic acid, magnesium or calcium stearate, and/orpolyethylene glycols. Suitable wetting agents include, for example,lecithin, polysorbates, and laurylsulfates. Generally, any effervescingagents, dyestuffs, and/or sweeteners known by those of ordinary skill inthe art can be used in the preparation of a pharmaceutical composition.For example, suitable sweetening agents include sucrose, fructose,lactose or aspartame, and suitable flavoring agents include peppermint,oil of wintergreen, or cherry flavoring. The aforementioned ingredientsare merely representative and one skilled in the art can envision otherbinders, excipients, sweetening agents, and the like.

[0188] When the unit dosage form is a capsule, it can contain, inaddition to ingredients of the above type, a liquid carrier (e.g.,vegetable oil or a polyethylene glycol). Various other ingredients canbe present as coatings or to otherwise modify the physical form of thesolid unit dosage form. For instance, tablets, pills, or capsules may becoated with gelatin, wax, shellac, or sugar, and the like. A syrup orelixir can contain the active compound, sucrose or fructose as asweetening agent, methyl and propyl parabens as preservatives, a dye andflavoring, such as cherry or orange flavor. Any material used inpreparing any unit dosage form should be pharmaceutically acceptable andsubstantially non-toxic in the amounts employed. In addition, the activecompound can be incorporated into sustained-release preparations anddevices including, but not limited to, those relying on osmoticpressures to obtain a desired release profile (e.g., the OROS drugdelivery devices as designed and developed by Alza Corporation, MountainView, Calif.).

[0189] Orally administered compositions can be prepared by any methodthat includes the step of bringing the active compound into intimateassociation with a carrier, which constitutes one or more necessary ordesirable ingredients. Generally, the compositions are prepared byuniformly and intimately admixing the active ingredient with liquidcarriers, finely divided solid carriers, or both, and then, ifnecessary, shaping the product into a desired form.

[0190] For example, a tablet can be prepared by compression or moldingtechniques, optionally, using one or more accessory ingredients.Compressed tablets can be prepared by compressing the active ingredientin a suitable machine into a free-flowing form, such as a powder orgranules. Thereafter, the compressed, free-flowing form optionally canbe mixed with binders, diluents, lubricants, disintegrating agents,effervescing agents, dyestuffs, sweeteners, wetting agents, andnon-toxic and pharmacologically inactive substances typically present inpharmaceutical compositions. The pharmaceutical composition can containabout 5 to about 95%, and preferably about 25 to about 90%, of acompound of the present invention. Molded tablets can be made by moldinga mixture of the powdered compound moistened with an inert liquiddiluent in a suitable machine.

[0191] Oral administration is the most convenient route ofadministration and avoids the disadvantages associated with other routesof administration. For patients suffering from a swallowing disorder orfrom impairment of drug absorption after oral administration, the drugcan be administered by other methods, such as parenterally, rectally orvaginally, transdermally, and nasally.

[0192] Parenteral administration is performed by preparing thecomposition containing the active compound. Solutions of the activecompound or its salts can be prepared in water, optionally mixed with anontoxic surfactant. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, triacetin, and mixtures thereof and inoils. Under ordinary conditions of storage and use, these preparationscontain a preservative to prevent the growth of microorganisms.

[0193] Pharmaceutical dosage forms suitable for parenteraladministration (e.g., subcutaneously, intravenously, intramuscularly, orby intraperitoneal injection or infusion) can include sterile aqueoussolutions or dispersions or sterile powders comprising the activeingredient which are adapted for the extemporaneous preparation ofsterile injectable or infusible solutions or dispersions, optionallyencapsulated in liposomes. In all cases, the ultimate dosage form shouldbe sterile, fluid, and stable under the conditions of manufacture andstorage.

[0194] The liquid carrier or vehicle can be a solvent or liquiddispersion medium comprising, for example, water, ethanol, a polyol(e.g., glycerol, propylene glycol, liquid polyethylene glycols, and thelike), vegetable oils, nontoxic glyceryl esters, and suitable mixturesthereof. The proper fluidity can be maintained, for example, by theformation of liposomes, by the maintenance of the required particle sizein the case of dispersions, or by the use of surfactants. The preventionof the action of microorganisms can be achieved by various antibacterialand antifungal agents, for example, parabens, chlorobutanol, phenol,sorbic acid, thimerosal, and the like. In many cases, it is preferableto include isotonic agents, for example, sugars, buffers, or sodiumchloride. Prolonged absorption of the injectable compositions can beachieved by use of agents that delay absorption, for example, aluminummonostearate and gelatin.

[0195] Sterile injectable solutions can be prepared by incorporating theactive compound in the required amount in the appropriate solvent withvarious of the other ingredients enumerated above, as required, followedby filter sterilization. In the case of sterile powders for thepreparation of sterile injectable solutions, the preferred methods ofpreparation are vacuum drying and the freeze drying techniques, whichyield a powder of the active ingredient plus any additional desiredingredient present in the previously sterile-filtered solutions.Sterilization of the powders also can be accomplished throughirradiation and aseptic crystallization methods known to persons skilledin the art.

[0196] For parenteral administration, the active compounds are presentedin aqueous solution in a concentration of about 0.1 to about 10%, morepreferably about 0.1 to about 7%, by weight. The solution can containother ingredients, such as emulsifiers, antioxidants, or buffers.

[0197] For topical administration, the present compounds can be appliedin neat form, e.g., when the compound is a liquid. However, it isdesirable to administer the compounds to the skin as compositions incombination with a dermatologically acceptable carrier, which can be asolid, semi-solid, or a liquid. Useful solid carriers include, but arenot limited to, finely divided solids such as talc, clay,microcrystalline cellulose, silica, alumina, and the like. Useful liquidcarriers include, but are not limited to, water, alcohols, glycols, andwater-alcohol/glycol blends, in which the present compounds can bedissolved or dispersed at effective levels, optionally with the aid of asurfactant. Adjuvants, such as fragrances and additional antimicrobialagents, can be added to optimize the properties for a given use. Theresultant liquid compositions can be applied topically by absorbentpads, used to impregnate bandages and other dressings, or sprayed ontothe affected area using pump-type or aerosol sprayers.

[0198] For administration by inhalation, compounds of the presentinvention can be delivered in the form of an aerosol spray presentationfrom pressurized packs or a nebulizer, with the use of a suitablepropellant. In the case of a pressurized aerosol, the dosage unit can bedetermined by providing a valve to deliver a metered amount. Capsulesand cartridges for use in an inhaler or insufflator can be formulatedcontaining a powder mix of the compound and a suitable powder base, suchas lactose or starch.

[0199] Compounds of the present invention also can be formulated inrectal compositions, such as suppositories or retention enemas, e.g.,containing conventional suppository bases. In addition to theformulations described previously, the compounds also can be formulatedas a depot preparation. Such long-acting formulations can beadministered by implantation (for example, subcutaneously orintramuscularly) or by intramuscular injection. Thus, for example, thecompounds can be formulated with suitable polymeric or hydrophobicmaterials (for example, as an emulsion in an acceptable oil) or ionexchange resins, or as sparingly soluble derivatives, for example, as asparingly soluble salt.

[0200] Generally, compounds of the invention are serotonin receptor(5-HT) ligands. The ability of a compound of the invention to act as a5-HT receptor agonist, partial agonist, or antagonist can be determinedusing in vitro and in vivo assays that are known in the art. Theinvention provides compounds of Formula (I) that act as either agonists,partial agonists, or as antagonists of one or more 5-HT receptorsubtypes.

[0201] As used herein, the terms “treat,” “treatment,” and “treating,”extend to prophylaxis, in other words “prevent,” “prevention,” and“preventing,” lowering, stopping, or reversing the progression orseverity of the condition or symptoms being treated. As such, the term“treatment” includes both medical therapeutic and/or prophylacticadministration, as appropriate. The terms “prevent,” “prevention,” and“preventing” refer to an administration of the pharmaceuticalcomposition to a person who has in the past suffered from theaforementioned diseases, disorders, or conditions, such as migraineheadaches, but is not suffering from the diseases, disorders, orconditions at the time of the composition's administration.

[0202] Compounds and pharmaceutical compositions suitable for use in thepresent invention include those wherein the active ingredient isadministered in an effective amount to achieve its intended purpose.More specifically, a “therapeutically effective amount” means an amounteffective to treat the disease, disorder, and/or condition.Determination of a therapeutically effective amount is well within thecapability of persons skilled in the art, especially in light of thedetailed disclosure provided herein.

[0203] A “therapeutically effective dose” refers to that amount of thecompound that results in achieving the desired treatment (or effect).Therapeutic efficacy of such compounds can be determined by standardpharmaceutical procedures in cell cultures or experimental animals,e.g., for determining the LD₅₀ (the dose lethal to 50% of thepopulation) and the ED₅₀ (the dose therapeutically effective in 50% ofthe population). The dosage can vary within this range depending uponthe dosage form employed, and the route of administration utilized.

[0204] The dosage regimen and amount for treating patients with thecompounds of this invention is selected in accordance with a variety offactors including, for example, the type, age, weight, sex, and medicalcondition of the patient, the severity of the condition, and the routeof administration. An ordinarily skilled physician or psychiatrist canreadily determine and prescribe an effective amount of the compound toprevent or arrest the progress of the condition. In so proceeding, thephysician or psychiatrist can employ relatively low initial dosages andsubsequently increasing the dose until a maximum response is obtained.

[0205] The compound is administered in unit dosage form, for example,containing about 0.05 to about 500 mg, preferably about 0.1 to about 250mg, and more preferably about 1 to about 150 mg, of active ingredientper unit dosage form. The desired dose can be presented in a singledose, or as divided doses administered at appropriate intervals, forexample, as two, three, four or more sub-doses per day. The sub-doseitself can be further divided, e.g., into a number of discrete looselyspaced administrations.

[0206] The compositions can be administered orally, sublingually,transdermally, or parenterally at dose levels of about 0.01 to about 150mg/kg, preferably about 0.1 to about 50 mg/kg, and more preferably about0.1 to about 10 mg/kg of mammal body weight.

[0207] The exact regimen for administration of the compounds andcompositions disclosed herein necessarily depends upon the needs of theindividual subject being treated, the patient type (i.e., human oranimal), the type of treatment and, of course, the judgment of theattending practitioner or physician. In practice, the physiciandetermines the actual dosing regimen which is most suitable for anindividual patient, and the dosage varies with the age, weight, andresponse of the particular patient. The above dosages are exemplary ofthe average case, but there can be individual instances in which higheror lower dosages are merited, and such are within the scope of thisinvention.

[0208] Specifically, for administration to a human in the curative orprophylactic treatment of the diseases, disorders, and conditionsidentified above, oral dosages of a compound of Formula (1) generallyare about 0.5 to about 1000 mg daily for an average adult patient (70kg). Thus, for a typical adult patient, individual tablets or capsulescontain 0.2 to 500 mg of active compound, in a suitable pharmaceuticallyacceptable vehicle or carrier, for administration in single or multipledoses, once or several times per day. Dosages for intravenous, buccal,or sublingual administration typically are 0.1 to 500 mg per single doseas required.

[0209] For veterinary use, a compound of Formula (I), or a nontoxic saltthereof, is administered as a suitably acceptable formulation inaccordance with normal veterinary practice. The veterinarian can readilydetermine the dosing regimen and route of administration that is mostappropriate for a particular animal.

[0210] In a particular embodiment, the invention includes apharmaceutical composition for the curative or prophylactic treatment ofdiseases, disorders, and conditions, where modulation of 5-HT receptorfunction is desired, the composition comprising a therapeuticallyeffective amount of a compound of Formula (I), or a pharmaceuticallyacceptable salt thereof, together with a pharmaceutically acceptablediluent or carrier.

[0211] Another embodiment of the present invention provides a method oftreating the above-noted diseases, disorders, and conditions in a humanor mammal body which comprises administering to said body atherapeutically effective amount of a compound of Formula (I).

[0212] According to another embodiment of the present invention, thereis provided a compound of Formula (I) or a pharmaceutically acceptablesalt thereof for use in medical therapy or diagnosis.

[0213] According to another embodiment of the present invention, thereis provided the use of a compound of Formula (I) for the manufacture ofa medicament for the treatment of the above-noted diseases, conditions,and disorders.

EXAMPLES

[0214] The following examples and preparations are provided toillustrate the invention but are not intended to limit the scope of theinvention.

[0215] The following abbreviations, and others known to those skilled inthe art, are used hereafter in the accompanying examples: μM(micromolar), Bn (benzyl), Bz (benzoyl), cm (centimeter), CH₂Cl₂(dichloromethane), DIC (diisopropylcarbodiimide), DMAP(4-dimethylamino-pyridine), DMF (N,N-dimethylformamide), LAH (lithiumaluminum hydride), DMSO (dimethyl sulfoxide), Et₃N (triethylamine),EtOAc (ethyl acetate), g (gram), IR (infrared), KBr (potassium bromide),mp (melting point), MeOH (methanol), MgSO₄ (magnesium sulfate), MHz(megahertz), h (hour), min (minute), mL (milliliter), mmol (millimole),NMR (nuclear magnetic resonance), psi (pounds per square inch), and THF(tetrahydrofuran).

[0216] Examples 1-350 illustrate the preparation of intermediatecompounds of formula (IV), which are useful for preparing compounds ofFormula (I).

[0217] Examples 351-465 illustrate the preparation of representativecompounds of Formula (I).

Examples 1-350

[0218] Preparation 1

[0219] Preparation of3-benzoyl-7-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0220] A mixture of3-benzoyl-7-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.517 g,1.40 mmol), potassium carbonate (0.77 g, 5.60 mmol), phenylboronic acid(0.194 g, 1.54 mmol), tetrakis(triphenylphosphine)palladium (0.16 g,0.14 mmol) in tetrahydrofuran (7.0 mL) and N,N-dimethylacetamide (7.0mL) was stirred at room temperature overnight. The mixture was filteredthrough Celite and the filtrate concentrated in vacuo to give an oil,which was subjected to column chromatography (silica gel, 10-50%EtOAc/heptane) to afford 0.44 g (86%) of the title compound as a solid:mp 198-200° C.; 1H NMR (400 MHz, CDCl₃) δ8.10, 7.67-7.60, 7.55-7.4,7.47-7.33, 7.18-7.14, 4.04-3.96, 3.72-3.63, 3.20-3.12, 2.93-2.80; IR(drift) 3258, 1602, 1464, 1430, 1327, 1295, 1239, 1185, 930, 761, 749,740, 711, 703, 696 cm⁻¹; MS (EI ) m/z 366 (M⁺); HRMS (FAB) calcd forC₂₅H₂₂N₂O+H: 367.1810, found: 367.1805; Anal. Calcd. for C₂₅H₂₂N₂O: C,81.94; H, 6.05; N, 7.64. Found: C, 81.37; H, 6.12; N, 7.57.

[0221] Preparation 2

[0222] Preparation of3-benzoyl-8-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0223] A mixture of3-benzoyl-8-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1.48 g,4.00 mmol) and tetrakis(triphenylphosphine)palladium (0.46 g, 0.40 mmol)in dimethoxyethane (10.0 mL) and a solution of phenylboronic acid (0.60g, 4.80 mmol) in dimethoxyethane (10.0 mL) and sodium carbonate (2 M,12.0 mL) were reacted in a manner similar to Preparation 1 to give abrown foam. Column chromatography (silica gel, 20-50% EtOAc/heptane)afforded 0.53 g (36%) of the title compound as a solid: mp 213-232° C.;¹H NMR (400 MHz, CDCl₃) δ8.13, 7.61, 7.44-7.40, 7.34-7.29, 4.07-3.98,3.70-3.63, 3.21-3.13, 2.92-2.83; ¹³C NMR (100 MHz, CDCl₃) δ171.7, 142.3,137.0, 135.9, 135.3, 134.9, 129.3, 128.7, 128.6, 128.3, 127.3, 126.5,126.4, 119.3, 117.7, 110.3, 109.0, 51.4, 45.8, 29.1, 26.2; IR (drift)3262, 1602, 1466, 1432, 1323, 1291, 1243, 811, 781, 763, 751, 743, 707,699, 627 cm⁻¹; MS (EI) m/z 366 (M⁺); HRMS (FAB) calcd for C₂₅H₂₂N₂O+H:367.1810, found: 367.1813; Anal. Calcd for C₂₅H₂₂N₂O: C, 81.94; H, 6.05;N, 7.64. Found: C, 81.43; H, 6.20; N, 7.42.

[0224] Preparation 3

[0225] Preparation of3-benzoyl-9-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0226] A mixture of3-benzoyl-9-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1.477 g,4.00 mmol) and tetrakis(triphenylphosphine)palladium (0.462 g, 0.40mmol) in dimethoxyethane (15.0 mL) and a solution of phenylboronic acid(0.585 g, 4.80 mmol) in dimethoxyethane (5.0 mL) and sodium carbonate (2M, 12.0 mL) were reacted in a manner similar to Preparation 1. Columnchromatography (silica gel, 60% EtOAc/hexane) afforded 0.817 g (56%) ofthe title compound as a solid: mp 78-79° C.; ¹H NMR (300 MHz, CDCl₃)δ8.10-7.85, 7.71-7.57, 7.43-7.29, 7.18-7.05, 4.16-4.04, 3.70-3.65,3.20-3.05, 2.95-2.80; MS (ESI+) m/z 367 (M⁺+H).

[0227] Preparation 4

[0228] Preparation of3-benzoyl-9-(4-methoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0229] A mixture of3-benzoyl-9-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.738 g,2.0 mmol) and tetrakis(triphenylphosphine)palladium (0.23 g, 0.20 mmol)in dimethoxyethane (5.0 mL) and a solution of 4-methoxyphenylboronicacid (0.365 g, 2.4 mmol) in dimethoxyethane (5.0 mL) and sodiumcarbonate solution (2 M, 7.0 mL) were reacted in a manner similar toPreparation 1. Column chromatography (silica gel, 20-60% EtOAc/heptane)afforded 0.29 g (37%) of the title compound as a yellow foam: mp140-145° C.; ¹H NMR (300 MHz, CDCl₃) δ7.92, 7.59-7.49, 7.43, 7.37-7.30,7.03-6.94, 4.09-3.98, 3.85, 3.75-3.65, 3.25-3.14, 2.95-2.85.

[0230] Preparation 5

[0231] Preparation of3-benzoyl-10-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0232] A mixture of3-benzoyl-10-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.517 g,1.40 mmol), potassium carbonate (0.77 g, 5.60 mmol), phenylboronic acid(0.194 g, 1.54 mmole), tetrakis(triphenylphosphine)palladium (0.16 g,0.14 mmol) in tetrahydrofuran (7.0 mL) and N,N-dimethylacetamide (7.0mL) reacted in a manner similar to Preparation 1. Column chromatography(silica gel, 10-50% EtOAc/heptane) afforded 0.49 g (95%) of the titlecompound as a solid: mp 223-226° C.; ¹H NMR (400 MHz, CDCl₃) δ8.25,7.57-7.23, 7.18-7.12, 6.98-6.89, 4.02-3.93, 3.76-3.67, 3.65-3.56,3.43-3.35, 3.18-3.12, 2.90-2.83, 2.66-2.58, 2.43-2.34; IR (drift) 3231,3203, 1602, 1501, 1468, 1433, 1352, 1336, 1249, 786, 758, 746, 740, 706,700 cm⁻¹; MS (EI) m/z 366 (M⁺); Anal. Calcd for C₂₅H₂₂N₂O: C, 81.94; H,6.05; N, 7.64. Found: C, 81.75; H, 6.07; N, 7.61.

[0233] Preparation 6

[0234] Preparation of3-benzoyl-10-(2-fluorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0235] A mixture of3-benzoyl-10-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.738 g,2.0 mmol) and tetrakis(triphenylphosphine)palladium (0.23 g, 0.20 mmol)in dimethoxyethane (5.0 mL) and a solution of 2-fluorophenylboronic acid(0.336 g, 2.4 mmol) in dimethoxyethane (5.0 mL) and sodium carbonate (2M, 7.0 mL) were-reacted in a manner similar to Preparation 1. Columnchromatography (silica gel, 20-50% EtOAc/heptane) afforded 0.33 g (43%)of the title compound as a solid: mp 241-244° C.; ¹H NMR (400 MHz,CDCl₃) δ8.20, 8.04, 7.31, 7.15, 7.04, 3.96, 3.83, 3.62, 3.42, 3.14,2.84, 2.71-2.69, 2.47, 2.31; IR (drift) 3236, 1603, 1501, 1485, 1469,1456, 1434, 1249, 1217, 795, 786, 759, 746, 733, 706 cm⁻¹; MS (EI) m/z384 (M⁺); HRMS (FAB) calcd for C₂₅H₂₁FN₂O+H: 385.1716, found: 385.1721;Anal. Calcd for C₂₅H₂₁FN₂O: C, 78.10; H, 5.51; N, 7.29. Found: C, 77.61;H, 5.60; N, 7.14.

[0236] Preparation 7

[0237] Preparation of3-benzoyl-10-(3,5-difluorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0238] A mixture of3-benzoyl-10-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.923 g,2.5 mmol) and tetrakis(triphenylphosphine)palladium (0.29 g, 0.25 mmol)in dimethoxyethane (10.0 mL) and a solution of 3,5-difluorophenylboronicacid (0.95 g of a 50% by weight solution in THF/H₂O, 3.0 mmol) andsodium carbonate (2 M, 12.0 mL) were reacted in a manner similar toPreparation 1. Column chromatography (silica gel, 1-5% MeOH/CHCl₃)afforded 1.03 g (100%) of a white solid: mp 198-201° C.; ¹H NMR (400MHz, CDCl₃) δ8.32, 7.40-7.28, 7.14, 6.98-6.80, 6.80-6.70, 4.04-3.94,3.83-3.73, 3.65-3.58, 3.60-3.50, 3.20-3.13, 2.94-2.84,2.71-2.60,2.45-2.36; R (drift) 3235, 3211, 1607, 1466, 1431, 1336, 1291,1117, 984, 864, 789, 751, 737, 704, 698 cm⁻¹; MS (EI) m/z 402 (M⁺);Anal. Calcd for C₂₅H₂₀F₂N₂O: C, 74.61; H, 5.01; N, 6.96. Found: C,74.57; H, 5.05; N, 6.99.

Example 1

[0239] Preparation of3-benzyl-7-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0240] To a solution of lithium aluminum hydride (1.27 g, 33.5 mmol) intetrahydrofuran (10.0 mL) was added a solution of3-benzoyl-7-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1.27 g,3.46 mmol) in tetrahydrofuran (25.0 mL) at 0° C. The mixture was stirredat room temperature overnight. Water (1.3 mL), 15% sodium hydroxidesolution (1.3 mL) and water (3.9 mL) were added sequentially and themixture was stirred for 30 min. Celite was added and the mixture wasfiltered through Celite. The filtrate was concentrated in vacuo to give1.12 g (92%) of the title compound: mp 78-79° C.; ¹H NMR (400 MHz,CDCl₃) δ7.92, 7.62, 7.51-7.26, 7.19-7.11, 3.83, 3.00-2.90; ¹³C NMR(100MHz, CDCl₃) δ139.5, 139.3,136.5, 132.4, 129.4, 129.1, 128.9, 128.3,128.2, 127.2, 127.0, 124.8, 121.0, 119.8, 117.0, 113.3, 60.7, 55.7,53.8, 28.6, 24.0; IR (drift) 2933, 2913, 2907, 2885, 2813, 1458, 1367,1345, 1336, 1325, 796, 760, 745, 730, 700 cm⁻¹; MS (EI) m/z 352 (M⁺);Anal. Calcd for C₂₅H₂₄N₂: C, 85.19; H, 6.86; N, 7.95. Found: C, 85.00;H, 6.89; N, 7.93.

Example 2

[0241] Preparation of3-benzyl-8-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0242] A solution of lithium aluminum hydride (1.40 g, 36.9 mmol) intetrahydrofuran (15.0 mL) and a solution of3-benzoyl-8-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1.40 g,3.82 mmol) in tetrahydrofuran (30.0 mL) at 0° C. were reacted in amanner similar to Example 1 to give an oil. Column chromatography(silica gel, 20-30% EtOAc/heptane) afforded 1.22 g (90%) of the titlecompound as a white solid: mp 176-177° C.; ¹H NMR (400 MHz, CDCl₃)δ7.74, 7.63-7.61, 7.48, 7.45-7.40, 7.36, 3.84, 3.00-2.92; ¹³C NMR (100MHz, CDCl₃) δ142.5, 139.3, 136.9, 135.2, 134.5, 128.9, 128.6, 128.5,128.3, 127.3, 127.0, 126.4, 119.1, 117.8, 112.8, 108.8, 60.7, 55.7,53.8, 28.6, 23.9; IR (drift) 3385, 3371, 1467, 1344, 1328, 1120, 1027,870, 820, 765, 756, 750, 735, 728, 698 cm⁻¹; MS (EI) m/z 352 (M⁺); Anal.Calcd for C₂₅H₂₄N₂: C, 85.19; H, 6.86; N, 7.95. Found: C, 85.24; H,6.89; N, 8.05.

Example 3

[0243] Preparation of3-benzyl-9-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0244] A solution of lithium aluminum hydride (0.17 g, 4.45 mmol) intetrahydrofuran (3.0 mL) and a solution of3-benzoyl-9-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.17 g,0.46 mmol) in tetrahydrofuran (5.0 mL) at 0° C. were reacted in a mannersimilar to Example 1 to give an oil. Column chromatography (silica gel,10-50% EtOAc/heptane) afforded 0.113 g (71%) of the title compound as anoil. ¹H NMR (300 MHz, CDCl₃) δ8.05, 7.66-7.57, 7.49, 7.45-7.30,7.13-7.04, 3.98, 3.18-2.97; MS (EI) m/z 366 (M⁺); HRMS (FAB) calcd forC₂₅H₂₄N₂+H: 353.2018, found: 353.2021.

Example 4

[0245] Preparation of3-benzyl-9-(4-methoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0246] A solution of lithium aluminum hydride (0.26 g, 6.86 mmol) intetrahydrofuran (5.0 mL) and a solution of3-benzoyl-9-(4-methoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(0.257 g, 0.65 mmol) in tetrahydrofuran (5.0 mL) were reacted in amanner similar to Example 1 to give 0.26 g (100%) of the title compoundas a white crystalline solid. ¹H NMR (300 MHz, CDCl₃) δ7.79, 7.58-7.54,7.46-7.31, 6.97, 3.89, 3.85, 3.10-2.94.

Example 5

[0247] Preparation of3-benzyl-10-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0248] A solution of lithium aluminum hydride (0.73 g, 19.2 mmol) intetrahydrofuran (10.0 mL) and a solution of3-benzoyl-10-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.73 g,2.0 mmol) in tetrahydrofuran (20.0 mL) at 0° C. were reacted in a mannersimilar to Example 1 to give 0.67 g (96%) of the title compound as awhite crystalline solid: mp 161-163° C.; ¹H NMR (400 MHz, CDCl₃) δ7.83,7.43-7.23, 7.14-7.10, 6.91, 3.70, 2.93-2.90, 2.86-2.83, 2.65-2.62,2.42-2.40; ¹³C NMR (100 MHz, CDCl₃) δ142.0, 139.3, 137.2, 135.0, 134.7,129.7, 128.9, 128.2, 127.6, 126.9, 126.6, 126.0, 121.6, 120.6, 113.6,109.5, 61.8, 55.8, 53.4, 28.5, 25.9; IR (drift) 3407, 2810, 1454, 1377,1347, 1334, 1319, 1175, 1120, 932, 785, 762, 754, 742, 700 cm⁻¹; MS (EI)m/z 352 (M⁺); HRMS (FAB) calcd for C₂₅H₂₄N₂+H: 353.2018, found:353.2039; Anal. Calcd for C₂₅H₂₄N₂: C, 85.19; H, 6.86; N, 7.95. Found:C, 84.83; H, 6.94; N, 7.83.

Example 6

[0249] Preparation of3-benzyl-10-(2-fluorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0250] A solution of lithium aluminum hydride (0.25 g, 6.59 mmol) intetrahydrofuran (5.0 mL) and a solution of3-benzoyl-10-(2-fluorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(0.247 g, 0.642 mmol) in tetrahydrofuran (5.0 ml) were reacted in amanner similar to Example 1 to give 0.15 g (63%) of the title compoundas pale yellow crystals: mp 157-159° C.; ¹H NMR (400 MHz, CDCl₃) δ7.86,7.37-7.24, 7.18-7.10, 6.91, 3.72, 3.00-2.90, 2.75-2.61, 2.57-2.48,2.42-2.33; ¹³C NMR (100 MHz, CDCl₃) δ161.9, 159.4, 137.6, 135.3, 132.5,130.0, 129.3, 128.7, 128.0, 127.5, 127.0, 124.1, 122.4, 121.0, 115.7,115.4, 114.1, 110.7, 62.0, 56.1, 53.9, 28.8, 24.9; IR (drift) 3405,2887, 2811, 1485, 1453, 1418, 1346, 1335, 1221, 1121, 924, 817, 782,757, 740 cm⁻¹; MS (EI) m/z 370 (M⁺); Anal. Calcd for C₂₅H₂₃FN₂: C,81.05; H, 6.26; N, 7.56. Found: C, 80.82; H, 6.35; N, 7.47.

Example 7

[0251] Preparation of3-benzyl-10-(3,5-difluorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0252] A solution of lithium aluminum hydride (0.60 g, 15.82 mmol) intetrahydrofuran (5.0 mL) and a solution of3-benzoyl-10-(3,5-difluoro)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(0.64 g, 1.59 mmol) in tetrahydrofuran (5.0 mL) were reacted in a mannersimilar to Example 1 to give 0.20 g (32%) of the title compound as whitecrystals: mp 172-175° C.; 1H NMR (400 MHz, CDCl₃) δ7.88, 7.37-7.23,7.11, 6.95-6.93, 6.88, 6.81-6.75, 3.73, 2.95-2.92, 2.88-2.84, 2.70-2.67,2.46-2.43; ¹³C NMR (100 MHz, CDCl₃) δ163.3, 161.1, 145.4, 139.2, 137.8,135.0, 132.2, 128.9, 128.7, 128.3, 127.0, 125.7, 121.3, 120.6, 113.2,112.8, 112.5, 110.4, 61.9, 55.8, 53.4, 28.6, 26.0; IR (drift) 3405,1619, 1590, 1455, 1350, 1334, 1117, 983, 865, 841, 793, 775, 755, 734,700 cm⁻¹; Anal. Calcd for C₂₅H₂₂F₂N₂: C, 77.30; H, 5.71; N, 7.21. Found:C, 77.29; H, 5.81; N, 7.18.

Example 8

[0253] Preparation of 7-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0254] A mixture of3-benzyl-7-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1.02 g,2.89 mmol), glacial acetic acid (2 drops) and Pd/C (10%, 0.6 g) inethanol (150 mL) was placed on a Parr hydrogenator under 50 psi ofhydrogen and shaken for 10 h. The reaction mixture was then filteredthrough Celite and concentrated in vacuo to give 0.97 g of a brown oil.Column chromatography (silica gel, 10% MeOH/CHCl₃+1% NH₄OH) gave 0.58 g(76%) of a brown foam: mp 143-174° C.; ¹H NMR (400 MHz, CDCl₃) δ7.99,7.64-7.61, 7.52-7.44, 7.40-7.36, 7.19-7.12, 3.12-3.06, 2.95-2.90; ¹³CNMR (100 MHz, CDCl₃) δ139.5, 136.6, 132.4, 129.5, 129.1, 128.3, 127.3,124.9, 121.0, 119.8, 117.0, 113.4, 50.4, 48.7, 32.9, 28.1; IR (drift)3052, 3028, 2923, 2827, 1485, 1460, 1430, 1409, 1332, 1320, 1180, 795,760, 743, 702 cm⁻¹; MS (EI) m/z 262 (M⁺); HRMS (FAB) calcd forC₁₈H₁₈N₂+H: 263.1548, found: 263.1543; Anal. Calcd forC₁₈H₁₈N₂.0.25C₂H₄O₂: C, 80.11; H, 6.90; N, 10.10. Found: C, 79.80; H,6.97; N, 10.17.

Example 9

[0255] Preparation of 8-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0256] A mixture of3-benzyl-8-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1.07 g, 3.0mmol), glacial acetic acid (2 drops) and Pd/C (10%, 0.6 g) in ethanol(150 mL) was reacted in a manner similar to Example 8 to give 0.40 g(51%) of the title compound as a tan crystalline solid: mp 220-222° C.;¹H NMR (400 MHz, DMSO-d₆) δ10.41, 7.61-7.59, 7.46, 7.42-7.38, 7.28-7.22,3.04-3.01, 2.96-2.94, 2.87-2.84; ¹³C NMR (100 MHz, DMSO-d₆) δ142.4,138:2, 135.3, 133.0, 128.5, 128.4, 126.8, 126.0, 117.9, 117.5, 111.8,108.8, 50.5, 48.8, 32.5, 28.0; IR (drift) 3305, 2929, 2918, 2893, 2827,1468, 1324, 1242, 869, 814, 787, 762, 753, 743, 700 cm⁻¹; MS (EI) m/z262 (M⁺); HRMS (FAB) calcd for C₁₈H₁₈N₂+H: 263.1548, found: 263.1543;Anal. Calcd for C₁₈H₁₈N₂.0.1 C₂H₄O₂: C, 81.46; H, 6.91; N, 10.44. Found:C, 81.11; H, 7.01; N, 10.35.

Example 10

[0257] Preparation of 9-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0258] A mixture of3-benzyl-9-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.22 g,0.62 mmol), glacial acetic acid-(2 drops) and Pd/C (10%, 0.15 g) inethanol (50.0 mL) was reacted in a manner similar to Example 8 to give0.13 g of an oil. Column chromatography (silica gel, 10-20%MeOH/CHCl₃+1% NH₄OH) gave an oil which precipitated from chloroform as asolid. Filtration gave 0.019 g (12%) of the title compound as ayellow-orange solid: mp >250° C.; ¹H NMR (300 MHz, DMSO-d₆) δ7.69-7.63,7.41, 7.34, 7.29-7.23, 3.38-3.24, 3.20-3.07; MS (EI) m/z 262 (M⁺); HRMS(FAB) calcd for C₁₈H₁₈N₂+H: 263.1548, found: 263.1550.

Example 11

[0259] Preparation of9-(4-methoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0260] A mixture of3-benzyl-9-(4-methoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(0.22 g, 0.62 mmol), 1 N hydrochloric acid (0.65 mL, 0.65 mmol) and Pd/C(10%, 0.24 g) in ethanol (50.0 mL) was reacted in a manner similar toExample 8 to give 0.168 g (80%) of a greenish solid: mp 258-260° C.; ¹HNMR (400 MHz, DMSO-d₆) δ11.08, 9.62, 7.64, 7.59, 7.31, 6.99, 3.79,3.37-3.27, 3.22-3.12; IR (drift) 2986, 2957, 2921, 2893, 2829, 2752,1514, 1476, 1456, 1273, 1250, 1239, 1180, 836, 800 cm⁻¹; MS (EI) m/z 292(M⁺); HRMS (FAB) calcd for C₁₉H₂₀N₂O+H: 293.1654, found: 293.1651; Anal.Calcd for C₁₉H₂₀N₂O. HCl: C, 69.40; H, 6.44; N, 8.52; Found: C, 68.37;H, 6.53; N, 8.27.

Example 12

[0261] Preparation of10-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0262] A mixture of3-benzyl-10-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.22 g,0.62 mmol), glacial acetic acid (2 drops) and Pd/C (10%, 0.11 g) inethanol (50.0 mL) was reacted in a manner similar to Example 8 to give0.198 g (90%) of a brown foam. Crystallization from ethyl acetate gave0.030 g of the title compound as a beige solid: mp >250° C.; ¹H NMR (300MHz, CDCl₃) δ7.97, 7.48-7.36, 7.16, 6.94, 3.12-3.08, 3.02-2.98,2.87-2.83, 2.47-2.43; IR (drift) 3053, 3025, 2927, 2895, 2833, 1458,1428, 1415, 1335, 1292, 1262, 790, 760, 751, 703 cm⁻¹; MS (EI) m/z 262(M⁺); HRMS (FAB) calcd for C₁₈H₁₈N₂+H: 263.1548, found 263.1550.

Example 13

[0263] Preparation of10-(2-fluorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0264] A mixture of3-benzyl-10-(2-fluorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(0.11 g, 0.30 mmol), 1 N hydrochloric acid (0.3 mL, 0.3 mmol) and Pd/C(10%, 0.2 g) in ethanol (50.0 mL) was reacted in a manner similar toExample 8 to give 0.017 g of the title compound as a pale green solid:mp >259° C. (dec.); ¹H NMR (300 MHz, DMSO-d₆) δ11.29, 9.29, 7.51-7.41,7.39-7.25, 7.08, 6.77, 3.33-3.20, 3.20-3.09, 3.09-2.99, 2.63-2.50; MS(EI) m/z 294 (M⁺).

Example 14

[0265] Preparation of10-(3,5-difluorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0266] A mixture of3-benzyl-10-(3,5-difluorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(0.35 g, 0.90 mmol), 1 N hydrochloric acid (0.9 mL, 0.9 mmol) and Pd/C(10%, 0.5 g) in ethanol (50 mL) was reacted in a manner similar toExample 8 to give 0.14 g of the title compound as a cream-colored solid:mp >267° C. (dec.); ¹H NMR (400 MHz, DMSO-d₆) δ11.42, 9.57, 7.37,7.30-7.25, 7.11-7.07, 6.84, 6.78-6.76, 3.35-3.27, 3.25-3.18, 3.16-3.08,2.63-2.56; IR (drift) 3259, 2956, 2861, 2811, 2778, 2699, 2641, 2455,1622, 1591, 1458, 1332, 1113, 985, 749 cm⁻¹; HRMS (FAB) calcd forC₁₈H₁₆F₂N₂+H: 299.1360, found: 299.1369.

[0267] Preparation 8

[0268] Preparation of3-tert-butyloxycarbonyl-10-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0269] In a 500 mL round-bottomed flask, a mixture of3-benzoyl-10-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (13.59 g,36.80 mmol), potassium hydroxide (10.32 g, 184.0 mmol), and ethyleneglycol (200.0 mL) were heated at 140° C. overnight. The mixture wascooled to 0° C., then dioxane (500.0 mL) and di-tert-butyl dicarbonate(9.64 g, 44.16 mmol) were added and stirred at room temperatureovernight. Dioxane was removed under reduced pressure and the resultingmixture was partitioned between chloroform and water. The aqueous layerwas extracted with chloroform (2×) and the combined organic layers wasdried (MgSO₄) and filtered. The filtrate was concentrated in vacuo todryness. The residue was subjected to column chromatography (silica gel,20-30% EtOAc/hexane) to give 12.74 g (95%) of a yellow solid: mp223-225° C.; ¹H NMR (400 MHz, CDCl₃) δ7.99, 7.23-7.19, 6.92, 3.77-3.65,3.56-3.47, 3.05-2.96; IR (drift) 3263, 1664, 1468, 1439, 1416, 1367,1352, 1332, 1300, 1190, 1170, 1162, 1115, 769, 737 cm⁻¹; MS (EI) m/z 364(M⁺); HRMS (EI) calcd for C₁₇H₂₁BrN₂O₂: 364.0787, found: 364:0794; Anal.Calcd for C₁₇H₂₁BrN₂O₂: C, 55.90; H, 5.80; N, 7.67. Found: C, 55.93; H,5.81; N, 7.66.

[0270] Preparation 9

[0271] Preparation of3-(tert-butyloxycarbonyl)-10-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0272] A mixture ofdicloro[1,1′-bis(diphenylphosphino)ferrocene]-palladium (II)dichloromethane adduct (4.83 g, 6.6 mmol), acetic acid potassium salt(6.5 g, 66.0 mmol), and bis(pinacolato)diboron (6.14 g, 24.2 mmol) wasflushed with nitrogen, and then dimethyl sulfoxide (125.0 mL) and3-tert-butyloxycarbonyl-10-bromo-1,2,3,4,5,6-tetrahydroazepino[4,5-b]indole(8.03 g, 22.0 mmol) were added. The mixture was heated at 80° C. for 18h. After cooling to room temperature, the mixture was partitionedbetween ethyl acetate and water. The aqueous layer was extracted withethyl acetate (2×). The combined ethyl acetate solution was concentratedin vacuo to dryness. The residue was subjected to column chromatography(silica gel, 1-3% MeOH/CHCl₃) to give 5.58 g (62%) of the title compoundas a white solid: mp 186-188° C.; ¹H NMR (300 MHz, CDCl₃) δ7.85, 7.49,7.34, 7.10, 3.75-3.60, 3.33-3.20, 3.06-2.95.

[0273] Compounds identified in Examples 15-46 were prepared according tothe following protocol (See FIG. 2):

[0274] 1. Pinacol boronate (5.10 g, 12.4 mmol)) and1,1′-bisdiphenylphosphine ferrocene (DPPF, 0.05 eq, 0.35 g, 0.62 mmol)were dissolved in 10% methanol in dioxane (degassed with argon) to a 100mL volume.

[0275] 2. Similarly, tris(dibenzylideneacetone)dipalladium (Pd₂dba₃,0.03 eq, 0.34 g, 0.37 mmol) was dissolved in 10% methanol in dioxane(degassed with argon) to a 50 mL volume.

[0276] 3. Cesium carbonate (1.5 eq, 0.12 g, 0.34 mmol) was weighed intolabeled, 20 mL vials, and stored at room temperature overnight. A 4 mmglass bead and the appropriate aryl bromides (˜3 eq) were added to thevials.

[0277] 4. The pinacol boronate/DPPF solution above was added (1.8 mL toeach vial) and the vials were purged with nitrogen and fitted with aTeflon-lined cap.

[0278] 5. In an argon-filled glove-box, the palladium solution was added(0.9 mL to each vial). The tightly-capped vials were then placed in aheater block (90° C.) and shaken at 250 RPM overnight.

[0279] 6. After cooling to ambient temperature, sulfonic acid resin(BioRad Ag®50W-X2, washed and dried, 5.2 meq/g dry weight) was added, 18eq to each vial (0.85 g) and also 1.8 mL of methanol. The vials thenwere capped and agitated at 250 RPM with heating at 60° C. for 2 hours.

[0280] 7. The vials then were cooled to ambient temperature and emptiedinto 25 mL fritted plastic syringe barrels affixed to a wash receivertank. The resin was washed into the syringe barrels with water andmethanol as required to have all the reagents in solution. A battery ofwashings then was used to ensure that all excess reagent was removedfrom the resin: 2×3 mL each of water, methanol, tetrahydrofuran, andmethylene chloride. The methanol and tetrahydrofuran washes can bealternated to swell and then shrink the resin to help expel reagentsfrom inside the resin. The vials that contained basic reagents (e.g.,pyridines) were also washed with 2M pyridine in methanol after themethanol washes.

[0281] 8. The syringe barrels then were racked above tared (using theBohdan weighing station) and labeled 20 mL vials, and the resin waswashed with 4M ammonium hydroxide in methanol (4×2 mL) andtetrahydrofuran (2×2 mL), gravity elution. Positive nitrogen pressurewas applied after the final elution (needle through a tight-fittingseptum).

[0282] Solvent was removed under vacuum with centrifugation to preventbumping (Genevac apparatus) and the masses were recorded (Bohdan).

[0283] 9. Hydrochloric acid (4N) in dioxane (excess) was added and theywere capped and shaken at ambient temperature overnight. Solvent wasremoved again under vacuum with centrifugation, and masses were recorded(using the Bohdan weighing station).

[0284] 10. Further purification was achieved through preparative HPLCseparation, and samples with >80% purity were reevaluated for CNSbinding activity as the formate salts.

Example 15

[0285] Preparation of10-(2-methoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0286] Following the protocol (Steps 1-10), above, making non-criticalvariations, the title compound was obtained. MS (EI) m/z 292.4 (MH⁺).

Example 16

[0287] Preparation of10-(3-methoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0288] Following the protocol (Steps 1-10), above, making non-criticalvariations, the title compound was obtained. MS (EI) m/z 292.5 (MH⁺).

Example 17

[0289] Preparation of10-(1,1′-biphenyl)-3-yl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0290] Following the protocol (Steps 1-10), above, making non-criticalvariations, the title compound was obtained. MS (EI) m/z 338.8 (MH⁺).

Example 18

[0291] Preparation of10-(4-phenoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0292] Following the protocol (Steps 1-10), above, making non-criticalvariations, the title compound was obtained. MS (EI) m/z 354.8 (MH⁺).

Example 19

[0293] Preparation of10-(4-methoxyphenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0294] Following the protocol (Steps 1-10), above, making non-criticalvariations, the title compound was obtained. MS (EI) m/z 292.5 (MH⁺).

Example 20

[0295] Preparation of10-(1,1′-biphenyl-)-4-yl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0296] Following the protocol (Steps 1-10), above, making non-criticalvariations, the title compound was obtained. MS (EI) m/z 338.9 (MH⁺).

Example 21

[0297] Preparation of10-(4-methylsulfanylphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0298] Following the protocol (Steps 1-10), above, making non-criticalvariations, the title compound was obtained. MS (EI) m/z 308.6 (MH⁺).

Example 22

[0299] Preparation of[4-(1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)phenyl](phenyl)methanonehydrochloride

[0300] Following the protocol (Steps 1-10), above, making non-criticalvariations, the title compound was obtained. MS (EI) m/z 367.0 (MH⁺).

Example 23

[0301] Preparation of10-(4-tert-butylphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0302] Following the protocol (Steps 1-10), above, making non-criticalvariations, the title compound was obtained MS (EI) m/z 318.8 (MH⁺).

Example 24

[0303] Preparation of10-(2-fluorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0304] Following the protocol (Steps 1-10), above, making non-criticalvariations, the title compound was obtained. MS (EI) m/z 280.5 (MH⁺).

Example 25

[0305] Preparation of 10-(3,4-difluorophenyl)-12,3,4,5,6-hexathydroazepino[4,5-b]indole hydrochloride

[0306] Following the protocol (Steps 1-10), above, making non-criticalvariations, the title compound was obtained. MS (EI) m/z 298.7 (MH⁺).

Example 26

[0307] Preparation of10-(3-fluorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride.

[0308] Following the protocol (Steps 1-10), above, making non-criticalvariations, the title compound was obtained. MS (EI) m/z 280.8 (MH⁺).

Example 27

[0309] Preparation of10-(3-trifluoromethylphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0310] Following the protocol (Steps 1-10), above, making non-criticalvariations, the title compound was obtained. MS (EI) m/z 330.9 (MH⁺).

Example 28

[0311] Preparation of10-(4-trifluoromethylphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0312] Following the protocol (Steps 1-10), above, making non-criticalvariations, the title compound was obtained. MS (EI) m/z 330.9 (MH⁺).

Example 29

[0313] Preparation of10-(3-chlorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0314] Following the protocol (Steps 1-10), above, making non-criticalvariations, the title compound was obtained. MS (EI) m/z 296.5/298.4(MH⁺).

Example 30

[0315] Preparation of10-(3,5-dichlorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0316] Following the protocol (Steps 1-10), above, making non-criticalvariations, the title compound was obtained. MS (EI) m/z 330.6/332.5(MH⁺).

Example 31

[0317] Preparation of10-(4-chlorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0318] Following the protocol (Steps 1-10), above, making non criticalvariations, the title compound was obtained. MS (EI) m/z 296.6/298.4(MH⁺).

Example 32

[0319] Preparation of10-(3-cyanophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0320] Following the protocol (Steps 1-10), above, making non-criticalvariations, the title compound was obtained. MS (EI) m/z 287.9 (MH⁺).

Example 33

[0321] Preparation of10-(4-cyanophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0322] Following the protocol (Steps 1-10), above, making non-criticalvariations, the title compound was obtained. MS (EI) m/z 287.8 (MH⁺).

Example 34

[0323] Preparation of[3-(1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)phenyl]acetonitrilehydrochloride

[0324] Following the protocol (Steps 1-10), above, making non-criticalvariations, the title compound was obtained. MS (EI) m/z 301.5 (MH⁺).

Example 35

[0325] Preparation of10-(1-naphthyl)-1,2,3,4,5,6-hexahydroazepino[4,5b]indole hydrochloride

[0326] Following the protocol (Steps 1-10), above, making non-criticalvariations, the title compound was obtained. MS (EI) m/z 312.8 (MH⁺).

Example 36

[0327] Preparation of10-(2-hydroxymethylphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0328] Following the protocol (Steps 1-10), above, making non-criticalvariations, the title compound was obtained. MS (EI) m/z 292.5 (MH⁺).

Example 37

[0329] Preparation of10-(4-hydroxymethylphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0330] Following the protocol (Steps 1-10), above, making non-criticalvariations, the title compound was obtained. MS (EI) m/z 292.5 (MH⁺).

Example 38

[0331] Preparation of10-(1,3-benzodioxol-5-yl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0332] Following the protocol (Steps 1-10), above, making non-criticalvariations, the title compound was obtained. MS (EI) m/z 306.6 (MH⁺).

Example 39

[0333] Preparation of10-(5-pyrimidinyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0334] Following the protocol (Steps 1-10), above, making non-criticalvariations, the title compound was obtained. MS (EI) m/z 264.5 (MH⁺).

Example 40

[0335] Preparation of10-(3,4-dimethoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0336] Following the protocol (Steps 1-10), above, making non-criticalvariations, the title compound was obtained. MS (EI) m/z 322.5 (MH⁺).

Example 41

[0337] Preparation of10-(3,5-difluorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0338] Following the protocol (Steps 1-10), above, making non-criticalvariations, the title compound was obtained. MS (EI) m/z 298.8 (MH⁺).

Example 42

[0339] Preparation of10-(4-n-butyloxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0340] Following the protocol (Steps 1-10), above, making non-criticalvariations, the title compound was obtained. MS (EI) m/z 335.0 (MH⁺).

Example 43

[0341] Preparation of10-(4-trifluoromethoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0342] Following the protocol (Steps 1-10), above, making non-criticalvariations, the title compound was obtained. MS (EI) m/z 346.9 (MH⁺).

Example 44

[0343] Preparation of10-(3,4-dichlorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0344] Following the protocol (Steps 1-10), above, making non-criticalvariations, the title compound was obtained. MS (EI) m/z 330.5/332.5(MH⁺).

Example 45

[0345] Preparation of10-(2-naphthyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole hydrochloride

[0346] Following the protocol (Steps 1-10), above, making non-criticalvariations, the title compound was obtained. MS (EI) m/z 313.3 (MH⁺).

Example 46

[0347] Preparation of10-(4-pyridinyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0348] Following the protocol (Steps 1-10), above, making non-criticalvariations, the title compound was obtained. MS (EI) m/z 264.2 (MH⁺).

Example 47

[0349] Preparation of3-benzyl-10-bromo-1,2,3,4,5,6-hexahydro-azepino[4,5-b]indole

[0350] To a suspension of lithium aluminum hydride (4.63 g, 121.9 mmol)in tetrahydrofuran (500.0 mL) was added aluminum chloride (16.3 g, 121.9mmol) at -20° C. followed by the addition of the suspension of3-benzoyl-10-bromo-1,2,3,4,5,6-hexahydro-azepino[4,5-b]indole (15.0 g,40.6 mmol) in tetrahydrofuran (100.0 mL). The mixture then was stirredat room temperature for 16 h and treated with 20% sodium hydroxidesolution (about 150 mL) until pH>13. After water was added, the aqueousmixture was extracted with ethyl acetate (3×). The combined ethylacetate solution was dried (MgSO₄) and filtered. The filtrate wasconcentrated in vacuo to dryness to give 13.6 g (94%) of colorless solidas the desired product: mp 179-180° C. (EtOAc/hexane); IR (KBr) 3410cm⁻¹; ¹H NMR (400 MHz, DMSO-d₆) δ11.12, 7.32-7.40, 7.23-7.27, 7.08,6.86, 3.75, 3.29-3.26, 2.92-2.89, 2.82-2.77; ¹³C NMR (100.6 MHz,DMSO-d₆) δ139.5, 139.2, 135.8, 128.5, 128.1, 126.7, 125.2, 122.8, 120.7,111.9, 111.7, 110.4, 60.5, 55.0, 53.0, 27.5, 24.1; MS (EI) m/z 354 (M⁺),356 (M⁺); HRMS cacld for C₁₉H₁₉BrN₂+H: 355.0810, found: 355.0803; Anal.Calcd. for C₁₉H₁₉BrN₂: C, 64.23; H, 5.39; N, 7.89. Found: C, 64.28; H,5.47; N, 7.87.

Example 48

[0351] Preparation ofbenzhydrylidene-(3-benzyl-1,2,3,4,5,6-hexahydro-azepino[4,5-b]indol-10-yl)amine

[0352] A mixture of3-benzyl-10-bromo-1,2,3,4,5,6-hexahydro-azepino[4,5-b]indole (0.71 g,2.00 mmol), benzophenone imine (0.44 g, 0.40 mL, 2.40 mmol),tris(dibenzylideneacetone)dipalladium(0) (0.037 g, 0.040 mmol),(S)-(−)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.075 g, 0.120mmol), and sodium tert-butoxide (0.269 g, 2.80 mmol) in toluene (20.0mL) was refluxed for 16 h. After cooling to room temperature, water andethyl acetate were added, and the pahases separated. The aqueous layerwas extracted with ethyl acetate (2×). The combined ethyl acetatesolution was dried (MgSO₄) and filtered. The filtrate was concentratedin vacuo to dryness and the residue was subjected to columnchromatography (silica gel, 30% EtOAc/hexane, 1% Et₃N) to afford ayellow fluffy solid as the title compound (0.855 g, 94%): mp >71° C.(dec.); ¹H NMR (300 MHz, CDCl₃) δ7.82-7.80, 7.65, 7.66-7.11, 6.82-6.79,6.73, 5.95, 3.78, 3.20-3.16, 2.90-2.78; MS (ESI+) m/z 456 (M⁺+H).

Example 49

[0353] Preparation of3-benzyl-10-amino-1,2,3,4,5,6-hexahydro-azepino[4,5-b]indole

[0354] To a solution ofbenzhydrylidene-(3-benzyl-1,2,3,4,5,6-hexahydro-azepino[4,5-b]indol-10-yl)amine(0.794 g, 1.74 mmol) in tetrahydrofuran was added 1 M hydrochloric acid(10.0 mL). The mixture was stirred at room temperature for 10 min, andthen tetrahydrofuran was removed in vacuo. The aqueous mixture wasextracted with ethyl acetate (2×). The acidic residue was basified withammonia and extracted with dichloromethane (3×). The combineddichloromethane solution was dried (MgSO₄) and filtered. The filtratewas concentrated in vacuo to dryness to give 0.416 g (82%) of the titlecompound: mp 164-165° C.; ¹H NMR (300 MHz, CDCl₃) δ7.76, 7.45-7.26,6.88, 6.74, 6.29, 3.86, 3.27-3.23, 3.06-2.97; MS (ESI+) m/z 292 (M⁺+H).

Example 50

[0355] Preparation ofN-(3-benzyl-1,2,3,4,5,6-hexahydro-azepino[4,5-b]indol-10-yl)-benzenesulfonamide

[0356] To a solution of3-benzyl-10-amino-1,2,3,4,5,6-hexahydro-azepino[4,5-b]indole (1.05 g,3.60 mmol) in pyridine (7.00 mL) was added benzenesulfonyl chloride(0.77 g, 4.40 mmol) at 0° C. After ten minutes at 0° C., the mixture wasstirred at room temperature for 16 h, and then poured into ice water.The mixure was filtered to give a sticky solid, which was dissolved inethyl acetate, washed successively with saturated ammonium chloride,saturated sodium bicarbonate, and brine, dried over magnesium sulphateand concentrated in vacuo to give a brown oil. The addition ofdichloromethane gave a brown solid which was recrystallized fromdichloromethane to give 0.62 g (40%) of yellow solid as the titlecompound: mp 164-165° C.; ¹H NMR (400 MHz, acetone-d₆) δ10.00, 8.40,7.70-7.67, 7.64-7.59 (m, 1 H), 7.51-7.48 (m, 2 H), 7.43-7.41 (m, 2 H),7.36-7.32 (t, 2 H), 7.27-7.24, 7.17, 6.79, 6.45, 3.75, 3.15-3.13,2.95-2.92, 2.80-2.77, 2.72-2.69; ¹³C NMR (100.6 MHz, acetone-d₆) δ142.1,140.7, 139.1, 139.0, 137.5, 137.4, 133.2, 129.6, 129.0, 128.1, 127.6,126.5, 120.4, 119.5, 113.3, 110.9, 62.5, 56.9, 54.7, 29.2, 26.4; IR(KBr) 3403, 1341, 1325, 1178, 1168 cm⁻¹; HRMS (FAB) calcd forC₂₅H₂₅N₃O₂S+H: 432.1746, found: 432.1747; Anal. Calcd for C₂₅H₂₅N₃O₂S:C, 69.58; H, 5.84; N. 9.74. Found: C, 69.41; H, 5.91; N, 9.64.

Example 51

[0357] Preparation ofN-(1,2,3,4,5,6-hexahydro-azepino[4,5-b]indol-10-yl)-benzenesulfonamide

[0358] A solution ofN-(3-benzyl-1,2,3,4,5,6-hexahydro-azepino[4,5-b]indol-10-yl)-benzenesulfonamide(0.26 g, 0.60 mmol) in ethanol (60.0 mL) was hydrogenated in thepresence of palladium on carbon (0.14 g) and 2 N hydrochloric acid (0.30mL, 0.60 mmol) at 50 psi for 24 h. More palladium on carbon (0.28 g) wasadded and hydrogenation was continued for 5 days. After filtrationthrough a pad of Celite, the filtrate was concentrated in vacuo todryness. The residue was subjected to column chromatography (10%MeOH/CHCl₃, 1% Et₃N) to give 0.037 g (18%) of yellowish solid as thetitle compound: mp 250-252° C.; IR (KBr) 3347, 1335, 1329, 1317, 1153cm⁻¹; ¹H NMR (300 MHz, MeOH-d₄) δ7.66-7.60, 7.57-47, 7.22, 6.79, 6.14,3.66-3.57, 3.45-3.38, 3.28-3.24; MS (ESI+) m/z 342 (M⁺+H); HRMS cacldfor C₁₈H₁₈N₂O+H: 342.1276, found: 342.1284; Anal. Calcd. forC₁₈H₁₉N₃O₂S: C, 63.32; H, 5.61; N, 12.31. Found: C, 62.99; H, 5.93; N,11.90.

[0359] Preparation 10

[0360] Preparation of3-benzoyl-9-phenoxy-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0361] A mixture of3-benzoyl-9-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1.00 g,2.71 mmol), phenol (0.51 g, 5.42 mmol), copper (I) oxide (0.019 g, 0.14mmol), and cesium carbonate (2.65 g, 8.12 mmol) in o-xylene was refluxedfor 24 h. After cooling to room temperature, the mixture was filteredand washed with ethyl acetate. The filtrate was concentrated in vacuo todryness, and the residue was subjected to column chromatography (silicagel, 60% EtOAc/hexane) to afford 0.11 g (10%) of a colorless solid asthe title compound: ¹H NMR (300 MHz, CDCl₃) δ7.42, 7.29-7.19, 7.03-6.86,4.12-3.91, 3.72-3.61, 3.20-3.04, 2.90-2.76; MS (ESI+) m/z 383 (M⁺+1).

[0362] Preparation 11

[0363] Preparation of3-benzoyl-10-phenoxy-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0364] A mixture of3-benzoyl-10-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1.85 g,5.00 mmol), phenol (0.94 g, 10.0 mmol), copper (I) oxide (0.036 g, 0.25mmol), and cesium carbonate (4.89 g, 15.0 mmol) in o-xylene was reactedin a similar manner to Preparation 10 to afford 0.55 g (29%) ofcolorless solid as the title compound: mp 179-182° C. (CH₂Cl₂/hexane);IR (KBr) 1601, 3226 cm⁻¹; ¹H NMR (300 MHz, CDCl₃) δ8.40-8.24, 7.43-7.34,7.05-6.90, 6.55-6.50, 4.00-3.90, 3.64-3.55, 3.29-2.84; ¹³C NMR (75.5MHz, CDCl₃) δ171.8, 158.1, 150.1, 137.0, 136.9, 135.0, 129.7, 129.3,128.6, 126.5, 122.6, 122.0, 118.1, 117.6, 110.1, 109.4, 106.5, 51.2,45.2, 28.9, 27.2; MS (EI) m/z 382 (M⁺); HRMS cacld for C₂₅H₂₂N₂O₂+H:383.1759, found: 383.1749; Anal. Calcd. for C₂₅H₂₂N₂O₂.1/2H₂O: C, 76.70;H, 5.92; N, 7.17. Found: C, 76.72; H, 5.79; N, 7.15.

Example 52

[0365] Preparation of3-benzyl-9-phenoxy-1,2,3,4,5,6-hexahydro-azepino[4,5-b]indole

[0366] To a solution of3-benzoyl-9-phenoxy-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.10 g,0.26 mmol) in tetrahydrofuran (5.0 mL) was added lithium aluminumhydride (0.10 g, 2.61 mmol). The resulted mixture was stirred at roomtemperature for 16 h. Water (0.10 mL), 15% sodium hydroxide solution(0.10 mL) and water (0.30 mL) were added sequentially. The mixture wasfiltered through a pad of Celite and the filtrate was concentrated invacuo to dryness. The residue was subjected to column chromatography(silica gel, 50% EtOAc/hexane with 1% Et₃N) to afford 0.093 g (99%) ofcolorless solid as the desired product. ¹H NMR (300 MHz, CDCl₃) δ7.77,7.21-7.44, 7.12, 6.95-7.04, 6.87, 3.00-2.91, 2.89-2.83.

Example 53

[0367] Preparation of3-benzyl-10-phenoxy-1,2,3,4,5,6-hexahydro-azepino[4,5-b]indole

[0368] A solution of3-benzoyl-10-phenoxy-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.55 g,1.45 mmol) in tetrahydrofuran (30.0 mL) and lithium aluminum hydride(0.56 g, 14.5 mmol) was reacted in a manner similar to Preparation 11 toafford 0.47 g (87%) of colorless solid as the desired product: mp168-170° C.(CH₂Cl₂/hexane); ¹H NMR (400 MHz, DMSO-d₆) δ11.0; 7.34-7.21,7.10, 7.01, 6.94, 6.84, 6.47, 3.69, 2.89-2.87, 2.84-2.81, 2.78-2.75,2.65-2.62; ¹³C NMR (100.6 MHz, DMSO-d₆) δ158.5, 147.8, 139.2, 137.4,136.9, 129.6, 128.4, 128.1, 126.7, 121.8, 120.5, 120.3, 116.4, 110.2,109.3, 107.4, 60.2, 55.4, 53.3, 27.6, 24.8; MS (EI) m/z 368 (M⁺); HRMScalcd for C₂₅H₂₄N₂O+H: 369.1967, found: 369.1961; Anal. Calcd. forC₂₅H₂₄N₂O: C, 81.49; H, 6.57; N, 7.60. Found: C, 81.12; H, 6.70; N,7.53.

Example 54

[0369] Preparation of9-phenoxy-1,2,3,4,5,6-hexahydro-azepino[4,5-b]indole hydrochloride

[0370] A solution of3-benzyl-9-phenoxy-1,2,3,4,5,6-hexahydro-azepino[4,5-b]indole (0.092 g,0.26 mmol) in ethanol (20.0 mL) was hydrogenated in the presence ofpalladium on carbon (0.04 g) and 2 N hydrochloric acid (0.13 mL, 0.26mmol,) at 50 psi for 16 h. After filtration through a pad of Celite, thefiltrate was concentratec in vacuo to dryness. The residue wasrecrystalized from EtOAc/MeOH to give 0.071 g (99%) of colorless solidas the desired product: mp >227° C. (dec.); ¹H NMR (400 MHz, DMSO-d₆)δ11.10, 9.60, 7.32-7.28, 7.11, 7.01, 6.88, 6.77, 3.36-3.27, 3.21-3.19,3.05-3.01; ¹³C NMR (100.6 MHz, DMSO-d₆) δ159.1, 148.5, 136.4, 131.5,129.6, 128.5, 121.7, 116.6, 114.0, 111.8, 109.7, 108.1, 46.6, 44.8,24.7, 20.8; MS (EI) m/z 278 (M⁺); HRMS cacld for C₁₈H₁₈N₂O+H: 279.1497,found: 279.1508; Anal. Calcd. for C₁₈H₁₈H₂O.HCl: C, 68.67; H, 6.08; N,8.90. Found: C, 67.95; H, 6.14; N, 8.99.

Example 55

[0371] Preparation of10-phenoxy-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole hydrochloride

[0372] A solution of3-benzyl-10-phenoxy-1,2,3,4,5,6-hexahydro-azepino[4,5-b]indole (0.28 g,0.75 mmol) in ethanol (20.0 mL) was hydrogenated reacted in a mannersimilar to Example 54 to give 0.23 g (98%) of colorless solid as thedesired product: mp >245° C. (dec.); ¹H NMR (400 MHz, DMSO-d₆) δ11.28,9.45, 7.34, 7.14, 7.06, 6.99, 6.91, 6.49, 3.29-3.27, 3.18-3.14; ¹³C NMR(100.6 MHz, DMSO-d₆) δ158.1, 148.3, 136.8, 135.2, 129.8, 122.3, 121.2,119.7, 116.9, 109.1, 108.5, 107.5, 46.3, 44.4, 24.4, 21.9; MS (EI) m/z278 (M⁺); HRMS cacld for C₁₈H₁₈N₂O+H: 279.1497, found: 279.1502; Anal.Calcd. for C₁₈H₁₈H₂O.HCl. 1/2H₂O: C, 66.76; H, 5.91; N, 8.65. Found: C,67.39; H, 5.98; N, 8.80.

[0373] Preparation 12

[0374] Preparation of3-(3-benzoyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-2-propyn-1-ol

[0375] A mixture of3-benzoyl-10-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (11.68 g,31.63 mmol), propargyl alcohol (3.25 mL, 60.20 mmol),tetrakistriphenylphosphine palladium(0) (1.83 g, 1.58 mmol), copper(I)iodide (0.151 g, 0.79 mmol), and pyrrolidine (100 mL) was allowed tostir under N₂. The mixture was warmed in a 93° C. oil bath and stirredunder reflux for 2.5 h. The mixture was cooled, concentrated andabsorbed onto SiO₂. Column chromatography (130 g SiO₂, 2.5% MeOH/CH₂Cl₂)provided 6.40 g of a brown foam. A second purification (Biotage 90 g,2.5% MeOH/CH₂Cl₂) provided pure product fractions which were collectedand evaporated. Crystallization from dichloromethane, methanol, ethylacetate, and hexanes provided 4.97 g of the title compound (mp 162-165°C.). ¹H NMR (CDCl₃) δ8.05-8.35, 7.35-7.50, 7.15-7.25, 6.95-7.10,7.40-7.60, 3.90-4.05, 3.55-3.70, 3.48, 3.25-3.40, 3.05-3.20, 2.75-2.85.

[0376] Preparation 13

[0377] Preparation of3-(3-benzoyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-1-propanol

[0378] A mixture of3-(3-benzoyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-2-propyn-1-ol(4.715 g, 13.69 mmol) and 10% Pd/C (0.548 g) in ethanol (75 mL) washydrogenated under 35 p.s.i. H₂ for 3.5 h. The mixture was filteredthrough celite, rinsed both ethanol, dichloromethane and evaporated.Crystallization from ethyl acetate/hexanes provided 4.230 g of the titlecompound (mp 144-147° C.). ¹H NMR (CDCl₃) δ8.20-8.55, 7.30-7.50,7.05-7.15, 6.95-7.05, 6.75-6.90, 3.90-4.10, 3.55-3.80, 3.35-3.45,2.90-3.20, 2.80-2.90, 1.75-2.00.

[0379] Preparation 14

[0380] Preparation of3-benzoyl-10-(3-phenoxypropyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0381] A dry flask was charged with3-(3-benzoyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-1-propanol(0.214 g, 0.61 mmol), triphenylphosphine (0.178 g, 0.68 mmol), phenol(0.064 g, 0.68 mmol) and tetrahydrofuran (5.0 mL). Under a N₂atmosphere, diethylazodicarboxylate (0.11 mL, 0.68 mmol) was added. Themixture stirred for 0.5 hours at room temperature and was evaporated invacuo. The ether product was purified by flash chromatography (90 gSiO₂, 1% MeOH/CH₂Cl₂) providing 0.145 g of the title compound (mp121-124° C.). IR (drift) 3236, 3210, 2940, 1604, 1496, 1466, 1430, 1298,1258, 1238, 10⁴6, 928, 751, 739, 704 cm⁻¹.

[0382] Example 56

[0383] Preparation of3-(1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)propyl phenyl etherhydrochloride

[0384] A mixture of3-benzoyl-10-(3-phenoxypropyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(0.265 g, 0.61 mmol) and potassium hydroxide (0.175 g, 3.12 mmol) inethylene glycol (10.0 mL) was heated under N₂ at 130° C. for 16 h. Themixture was cooled to rt, poured into water (50 mL) and extracted withdichloromethane (3×75 mL). The combined organics were washed with water,brine, dried over anhydrous sodium sulfate and evaporated in vacuo. Theresidue was treated with methanolic hydrochloric acid and evaporated invacuo. Recrystallization from ethyl acetate and hexanes provided 0.132 gof the title compound (mp 215-218° C.). ¹H NMR (DMSO-d₆) δ11.05, 7.27,7.10, 6.80-7.00, 6.70, 4.00, 2.95-3.50, 1.85-2.08.

Example 57

[0385] Preparation of3-(1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)propyl 2-naphthylether hydrochloride

[0386] Following the procedures of Preparation 14 and Example 56, makingnon-critical variations, and using 2-naphthol, the title compound wasobtained. HRMS (FAB) calcd for C₂₅H₂₆N₂O(MH⁺) 371.2123, found 371.2123.

Example 58

[0387] Preparation of3-(1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)propyl 1-naphthylether hydrochloride

[0388] Following the procedures of Preparation 14 and Example 56, makingnon-critical variations, and using 1-naphthol, the title compound wasobtained. HRMS (FAB) calcd for C₂₅H₂₆N₂O(MH⁺) 371.2123, found 371.2134.

Example 59

[0389] Preparation of10-[3-([1,1′-biphenyl]-4-yloxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0390] Following the procedures of Preparation 14 and Example 56, makingnon-critical variations, starting with the appropriate phenol, the titlecompound was obtained. HRMS (FAB) calcd for C₂₇H₂₈N₂O(MH⁺) 397.2280,found 397.2288.

Example 60

[0391] Preparation of10-[3-(3-methoxyphenoxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0392] Following the procedures of Preparation 14 and Example 56, makingnon-critical variations, starting with the appropriate phenol, the titlecompound was obtained. HRMS (FAB) calcd for C₂₂H₂₆N₂O₂ (MH⁺) 351.2072,found 351.2073.

Example 61

[0393] Preparation of10-[3-(4-methoxyphenoxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0394] Following the procedures of Preparation 14 and Example 56, makingnon-critical variations, starting with the appropriate phenol, the titlecompound was obtained. HRMS (FAB) calcd for C₂₂H₂₆N₂O₂ (MH⁺) 351.2072,found 351.2077.

Example 62

[0395] Preparation of10-[3-(4-chlorophenoxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0396] Following the procedures of Preparation 14 and Example 56, makingnon-critical variations, starting with the appropriate phenol, the titlecompound was obtained. HRMS (FAB) calcd for C₂₁H₂₃ClN₂O(MH⁺) 355.1577,found 355.1584.

Example 63

[0397] Preparation of10-[3-(3-chlorophenoxy)propyl]-1,2,3,4,5,6-hexahydroazepino-[4,5-b]indolehydrochloride

[0398] Following the procedures of Preparation 14 and Example 56, makingnon-critical variations, starting with the appropriate phenol, the titlecompound was obtained. HRMS (FAB) calcd for C₂₁H₂₃ClN₂O(MH⁺) 355.1577,found 355.1581.

Example 64

[0399] Preparation of10-[3-(2-chlorophenoxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0400] Following the procedures of Preparation 14 and Example 56, makingnon-critical variations, starting with the appropriate phenol, the titlecompound was obtained. HRMS (FAB) calcd for C₂₁H₂₃ClN₂O(MH⁺) 355.1577,found 355.1570.

Example 65

[0401] Preparation of10-[3-(2,4-dichlorophenoxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0402] Following the procedures of Preparation 14 and Example 56, makingnon-critical variations, starting with the appropriate phenol, the titlecompound was obtained. MS (EI) m/z 389 (MH⁺).

Example 66

[0403] Preparation of10-[3-(2,5-dichlorophenoxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0404] Following the procedures of Preparation 14 and Example 56, makingnon-critical variations, starting with the appropriate phenol, the titlecompound was obtained. MS (EI) m/z 389 (MH⁺).

Example 67

[0405] Preparation of10-[3-(4-fluorophenoxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0406] Following the procedures of Preparation 14 and Example 56, makingnon-critical variations, starting with the appropriate phenol, the titlecompound was obtained. MS (EI) m/z 339 (MH⁺).

Example 68

[0407] Preparation of10-[3-(4-methylphenoxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0408] Following the procedures of Preparation 14 and Example 56, makingnon-critical variations, starting with the appropriate phenol, the titlecompound was obtained. MS (EI) m/z 335 (MH⁺).

Parallel synthesis

[0409] A modified version of the above mentioned scheme was utilized forthe parallel synthesis. The Sonogashira coupling and reduction to thealkane followed as previously mentioned to obtain3-(3-benzoyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-1-propanol.Hydrolysis of the amide functionality under basic conditions led to thefree base. Protection in situ as the tert-butyl carbamate and standardMitsunobu reaction conditions using various aryl alcohols provided thecorresponding aryl ethers. Immediate deprotection of the tert-butylcarbamate using DOWEXO® ion exchange resin (5.2 meq/g), removal of thereaction byproducts and excess reagents through successive washing,release from the resin through addition of excess base, and trapping thefreebase as the hydrochloride salt led to the desired compounds.

[0410] Preparation 15

[0411] Preparation of tert-butyl10-(3-hydroxypropyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0412] A mixture of3-(3-benzoyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-1-propanol(1.515 g, 4.35 mmol), potassium hydroxide (2.440 g, 43.47 mmol), andethylene glycol (50 mL) was allowed to stir under N₂ in an oil bath. Thebath temperature was raised to 158° C. and stirred for 16 h. The mixturewas then cooled to rt, diluted with H₂O (25 mL), dioxane (25 mL) andcooled further in an ice bath. Di-tert-butyldicarbonate (1.218 g 5.581mmol) was added in two portions and the ice bath was removed. After 2 h,the room temperature mixture was poured into H₂O (about 300 mL) andextracted with ethyl acetate (3×50 mL). Evaporation of the combinedorganic layers provided a brown oil. Crystallization from ethyl acetateand hexanes provided the title compound 0.825 as a tan solid (mp166-168° C.): IR (drift) 3242, 3218, 2974, 2943, 2930, 2873, 1667, 1484,1452, 1417, 1365, 1239, 1171, 1037, 749 cm⁻¹.

Example 69

[0413] Preparation of4-[3-(1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)propoxy]benzonitrilehydrochloride

[0414] To a 25 mL scintillation vial containing a glass bead was added4-cyanophenol (0.033 g, 0.277 mmol), a solution (0.250 M) of tert-butyl10-(3-hydroxypropyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxyl ate (1.0 mL, 0.250 mmol) in tetrahydrofuran, a solution(0.275 M) of triphenylphosphine (1.0 mL, 0.275 mmol) in tetrahydrofuran,and diethylazodicarboxylate (43.5 μl, 0.275 mmol). The vial was cappedand orbitally shaken for 30 h. The mixture then was diluted withdichloromethane (1 mL) and methanol (1 mL). DOWEX® ion exchange resin(5.2 meq/gram, 0.5-0.75 g) was added and the mixtures were capped andshaken orbitally at 40° C. for 3 h. The mixture was filtered and theresin was washed (2×=0 each) with dichloromethane, methanol, water, andtetrahydrofuran. The product then was eluted using a 4 N solution ofammonium hydroxide in methanol. Evaporation provided a residue whichupon treatment with methanolic hydrochloric acid and evaporation led tothe title compound. MS (EI) for m/z 346 (MH⁺).

Example 70

[0415] Preparation of3-(1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)propyl 2-pyridinylether dihydrochloride

[0416] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 322 (MH⁺).

Example 71

[0417] Preparation of 2-bromophenyl3-(1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)propyl etherhydrochloride

[0418] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 399 (MH⁺).

Example 72

[0419] Preparation of3-(1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)propyl 2-iodophenylether hydrochloride

[0420] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 447 (MH⁺).

Example 73

[0421] Preparation of 2-ethylphenyl3-(1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)propyl etherhydrochloride

[0422] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 349 (MH⁺).

Example 74

[0423] Preparation of10-[3-(2-isopropylphenoxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0424] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 363 (MH⁺).

Example 75

[0425] Preparation of2-[3-(1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)propoxy]benzonitrilehydrochloride

[0426] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 346 (MH⁺).

Example 76

[0427] Preparation of3-(1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)propyl 3-pyridinylether dihydrochloride

[0428] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 322 (MH⁺).

Example 77

[0429] Preparation of10-[³-(3-fluorophenoxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0430] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 339 (MH⁺).

Example 78

[0431] Preparation of 3-bromophenyl3-(1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)propyl etherhydrochloride

[0432] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 399 (MH⁺).

Example 79

[0433] Preparation of3-(1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)propyl 3-iodophenylether hydrochloride

[0434] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 447 (MH⁺).

Example 80

[0435] Preparation of10-[3-(3-isopropylphenoxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0436] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 363 (MH⁺).

Example 81

[0437] Preparation of10-{3-[3-(trifluoromethyl)phenoxy]propyl}-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0438] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 389 (MH⁺).

Example 82

[0439] Preparation of10-{3-[3-(trifluoromethoxy)phenoxy]propyl}-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride.

[0440] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 405 (MH⁺).

Example 83

[0441] Preparation of 3-ethylphenyl3-(1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)propyl etherhydrochloride

[0442] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 349 (MH⁺).

Example 84

[0443] Preparation of10-[3-(3-tert-butylphenoxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0444] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 377 (MH⁺).

Example 85

[0445] Preparation of3-(1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)propyl 4-pyridinylether dihydrochloride

[0446] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 322 (MH⁺).

Example 86

[0447] Preparation of10-[3-(4-methoxyphenoxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0448] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 351 (MH⁺).

Example 87

[0449] Preparation of10-{3-[4-(benzyloxy)phenoxy]propyl}-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0450] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 427 (MH⁺).

Example 88

[0451] Preparation of 4-bromophenyl3-(1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)propyl etherhydrochloride

[0452] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 399 (MH⁺).

Example 89

[0453] Preparation of3-(1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)propyl 4-iodophenylether hydrochloride

[0454] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 447 (MH⁺).

Example 90

[0455] Preparation of 4-ethylphenyl3-(1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)propyl etherhydrochloride

[0456] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 349 (MH⁺).

Example 91

[0457] Preparation of10-[3-(4-isopropylphenoxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0458] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 363 (MH⁺).

Example 92

[0459] Preparation of10-{3-[(4′-bromo[1,1′-biphenyl]-4-yl)oxy]propyl}-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0460] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 477 (MH⁺).

Example 93

[0461] Preparation of10-[3-(2,3-difluorophenoxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0462] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 357 (MH⁺).

Example 94

[0463] Preparation of10-[3-(2,4-dibromophenoxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0464] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 479 (MH⁺).

Example 95

[0465] Preparation of10-[3-(2,4-difluorophenoxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0466] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 357 (MH⁺).

Example 96

[0467] Preparation of10-[3-(2-methoxy-4-methylphenoxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0468] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 365 (MH⁺).

Example 97

[0469] Preparation of10-[3-(4-iodo-2-methylphenoxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0470] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 461 (MH⁺).

Example 98

[0471] Preparation of10-[3-(2,5-difluorophenoxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0472] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 357 (MH⁺).

Example 99

[0473] Preparation of10-[3-(2-chloro-5-methylphenoxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0474] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 369 (MH⁺)

Example 100

[0475] Preparation of10-[3-(2-isopropyl-5-methylphenoxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0476] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 377 (MH⁺).

Example 101

[0477] Preparation of10-[3-(2,6-difluorophenoxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0478] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 357 (MH⁺).

Example 102

[0479] Preparation of10-[3-(2,6-dichlorophenoxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0480] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 389 (MH⁺).

Example 103

[0481] Preparation of10-[3-(2,6-dimethylphenoxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0482] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 349 (MH⁺).

Example 104

[0483] Preparation of10-[3-(2-fluoro-6-methylphenoxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0484] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 369 (MH⁺).

Example 105

[0485] Preparation of3-(1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)-1-propanolhydrochloride

[0486] Following the procedure of Example 69, except using no phenol,the title compound was obtained. MS (EI) m/z 245 (MH⁺).

Example 106

[0487] Preparation of10-[3-(2,3,6-trimethylphenoxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0488] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 363 (MH⁺).

Example 107

[0489] Preparation of10-[3-(mesityloxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0490] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 363 (MH⁺).

Example 108

[0491] Preparation of10-[3-(2,6-dibromo-4-methylphenoxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0492] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 493 (MH⁺).

Example 109

[0493] Preparation of10-[3-(4-chloro-3-fluorophenoxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0494] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 373 (MH⁺).

Example 110

[0495] Preparation of10-[3-(4-chloro-3-methylphenoxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0496] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 369 (MH⁺).

Example 111

[0497] Preparation of10-[3-(3-chloro-4-fluorophenoxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0498] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 373 (MH⁺).

Example 112

[0499] Preparation of10-[3-(1,3-benzodioxol-5-yloxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0500] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 365 (MH⁺).

Example 113

[0501] Preparation of 10-[3(3,5-dichlorophenoxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0502] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 389 (MH⁺).

Example 114

[0503] Preparation of10-[3-(3,5-dimethylphenoxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0504] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 349 (MH⁺).

Example 115

[0505] Preparation of10-[3-(3,5-dimethoxyphenoxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride.

[0506] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 381 (MH⁺).

Example 116

[0507] Preparation of10-[3-(5,6,7,8-tetrahydro-1-naphthalenyloxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0508] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 375 (MH⁺).

Example 117

[0509] Preparation of10-{3-[(2,4-dichloro-1-naphthyl)oxy]propyl}-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0510] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 439 (MH⁺).

Example 118

[0511] Preparation of10-{3-[(4-methoxy-1-naphthyl)oxy]propyl}-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0512] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 401 (MH⁺).

Example 119

[0513] Preparation of10-{3-[(4-chloro-1-naphthyl)oxy]propyl}-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0514] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 405 (MH⁺).

Example 120

[0515] Preparation of10-{3-[(1,6-dibromo-2-naphthyl)oxy]propyl}-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0516] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 529 (MH⁺).

Example 121

[0517] Preparation of10-{3-[(1-bromo-2-naphthyl)oxy]propyl}-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0518] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 449 (MH⁺).

Example 122

[0519] Preparation of10-[3-(2,3,4,5,6-pentafluorophenoxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0520] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 411 (MH⁺).

Example 123

[0521] Preparation of10-[3-(5-isoquinolinyloxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indoledihydrochloride

[0522] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 372 (MH⁺).

Example 124

[0523] Preparation of10-[3-([1,1′-biphenyl]-2-yloxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0524] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 397 (MH⁺).

Example 125

[0525] Preparation of10-{3-[(5-chloro-8-quinolinyl)oxy]propyl}-1,2,3,4,5,6-hexahydroazepino[4,5-b]indoledihydrochloride

[0526] Following the procedure of Example 69, making non-criticalvariations, starting with the appropriate phenol, the title compound wasobtained. MS (EI) m/z 406 (MH⁺).

[0527] Preparation 16

[0528] Preparation of tert-butyl1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0529] Di-tert-butyldicarbonate (6.33 g, 29.0 mmol) was added to amixture of 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (5.40 g, 29.0 mmol)in dichloromethane (20 mL). The mixture was stirred for 48 h, thenpoured into water (50 mL), and extracted with dichloromethane (3×40 mL).The combined organics were dried over sodium sulfate, evaporated invacuo and crystallized from ethyl acetate to provide 5.71 g of the titlecompound, the structure of which is shown in FIG. 6 as (22).

[0530] Preparation 17

[0531] Preparation of tert-butyl6-(2-ethoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0532] To a mixture of tert-butyl1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (3.557 g, 12.42mmol) and N,N-dimethylformamide (30 mL) was added 60% sodium hydride(0.596 g, 14.90 mmol). The mixture stirred for 1 h, and then cooled in a0° C. bath. Ethyl bromoacetate was added, and the mixture warmed to roomtemperature. Water then was added and the mixture was evaporated invacuo. The residue was taken up in ethyl acetate and washed with water.Evaporation and trituration with hexanes provided 3.289 g of the titlecompound, the structure of which is shown in FIG. 6 as (23) (where n=1).

[0533] Preparation 18

[0534] Preparation of tert-butyl6-(2-hydroxyethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0535] A chilled (0° C.) mixture of tert-butyl6-(2-ethoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylatein tetrahydrofuran (30 mL) was treated over 1 h with 1 Mdiisobutylaluminum hydride (19.0 mL, 19.0 mmol) in dichloromethane.After 1.5 h, ice was added and the mixture was allowed to wann to rt.The mixture was evaporated in vacuo and the residue was partitionedbetween ethyl acetate and water. The organic phase was filtered throughcelite, dried, and evaporated in vacuo to provide 2.479 g of the titlecompound, the structure of which is shown in FIG. 6 as (24) (where n=1).

[0536] Preparation 19

[0537] Preparation of tert-butyl6-[2-(3-methoxyphenoxy)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0538] A mixture of tert-butyl6-(2-hydroxyethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.459 g, 1.39 mmol), 3-methoxyphenol (0.170 g, 1.39 mmol) andtriphenylphosphine (0.364 g, 1.39 mmol) in tetrahydrofuran (15 mL) wastreated with diethylazodicarboxylate (0.243 g, 1.39 mmol). The mixturestirred for 24 h, and then was evaporated in vacuo. Columnchromatography (90 g SiO₂, 70% hexanes/30% ethyl acetate) provided anoil which was extracted into ethyl acetate and washed with 1 N sodiumhydroxide. The organic phase was dried and evaporated to provide thetitle compound and was used without isolation. The structure of thetitle compound is shown in FIG. 6 as (25), where n=1 and Ar=3-MeOphenyl.

Example 126

[0539] Preparation of6-[2-(3-methoxyphenoxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolemaleate

[0540] A mixture of tert-butyl6-[2-(3-methoxyphenoxy)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.447 g, 1.02 mmol) in methanolic hydrochloric acid was warmed in a 50°C. bath for 1.5 h. The mixture was evaporated, taken up in ethylacetate, then washed with 1 N sodium hydroxide. The organic phase wasdried and evaporated to provide an oil. The oil was diluted withmethanol and a solution of maleic acid in methanol was added.Evaporation and crystallization of the residue from methanol, ethylacetate, and hexanes, afforded 0.347 g of the title compound(mp=131-133° C.).

Example 127

[0541] Preparation of 3-nitrophenyl2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethyl etherhydrochloride

[0542] Following the procedure of Example 126, making non-criticalvariations, starting with the appropriate phenol, and trapping as thehydrochloride salt, the title compound was obtained. HRMS (FAB) calcdfor C₂₀H₂₁N₃O₃ (MH⁺) 352.1661, found 352.1681.

Example 128

[0543] Preparation of6-[2-(3-isopropylphenoxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolemaleate

[0544] Following the procedure of Example 126, making non-criticalvariations, starting with the appropriate phenol, and trapping as themaleate salt, the title compound was obtained. HRMS (FAB) calcd forC₂₃H₂₈N₂O (MH⁺) 349.2280, found 349.2272.

Example 129

[0545] Preparation of 4-pyridinyl2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethyl etherdihydrochloride

[0546] Following the procedure of Example 126, making non-criticalvariations, starting with the appropriate phenol, and trapping as thedihydrochloride salt, the title compound was obtained. HRMS (FAB) calcdfor C₁₉H₂₁N₃O (MH⁺) 308.1763, found 308.1759.

[0547] Preparation 20

[0548] Preparation of3-tert-butyloxycarbonyl-6-(3-chloropropyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0549] Sodium hydride (335 mg, 60%) was added to a solution of3-tert-butyloxycarbonyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1.99g) and DMF (21.0 mL) at 0° C. The solution was stirred at 0° C. for 30min and then 1-bromo-3-chloropropane (0.74 mL) was added. The solutionwas stirred at 0° C. for 1 h and 16 h at room temperature. The solutionwas diluted with EtOAc, which was washed with water (3×20 mL). Thecombined aqueous layers were extracted with EtOAc (2×20 mL). Thecombined organic layers were dried (MgSO₄), filtered, and concentrated.The crude material was purified by chromatography (Biotage, silica gel,4:1-1:1 hexane:EtOAc) to give 1.38 g of the title compound as an oil: ¹HNMR (300 MHz, CDCl₃) δ7.50, 7.10-7.40, 4.28, 3.55-3.82, 3.52, 2.95-3.10,2.15-2.30, 1.51; MS (ESI) m/z 363 (M⁺).

[0550] Preparation 21

[0551] Preparation of3-tert-butyloxycarbonyl-6-(3-phenoxypropyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0552] A mixture of3-tert-butyloxycarbonyl-6-(3-chloropropyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(213 mg), phenol (90 mg), DMF (2.0 mL), and K₂CO₃ (81 mg) was heated at100° C. for 16 h, then allowed to cool to room temperature. The mixturewas diluted with EtOAc (50 mL), then washed with water (3×10 mL). Theorganic layer was dried (MgSO₄), filtered, and concentrated.Purification by flash chromatography (silica gel, 3:1 hexane:EtOAc) gave205 mg of the title compound as an oil: ¹H NMR (300 MHz, CDCl₃)δ7.45-7.55, 6.8-7.35, 4.33, 3.90, 3.55-3.75, 2.90-3.10, 2.12-2.28, 1.49;MS (ESI) m/z 421 (M⁺).

Example 130

[0553] Preparation of6-(3-phenoxypropyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole maleate

[0554] A solution of3-tert-butyloxycarbonyl-6-(3-phenoxypropyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(205 mg), CH₂Cl₂ (4.0 mL), and TFA (2.0 mL) was stirred at 0° C. for 1.5h, then concentrated. The residue was partitioned between CH₂Cl₂ and aq.NaHCO₃. The organic layers were dried (MgSO₄), filtered, andconcentrated to give 70 mg of the desired product. The maleic acid saltwas prepared in ether, and the crude product triturated with ether toprovide the title compound: ¹H NMR (300 MHz, CDCl₃) δ7.40-7.50,7.20-7.35, 7.00-7.15, 6.95, 6.80-6.90, 4.33, 3.87, 2.85-3.10, 2.10-2.25.

Example 131

[0555] Preparation of6-[3-(3-chlorophenoxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolemaleate

[0556] Following Example 130, but starting with 3-chlorophenol, andmaking non-critical variations, the title compound was obtained: ¹H NMR(300 MHz, CDCl₃) δ7.41-7.51, 7/05-7.30, 6.65-6.95, 4.31, 3.84,2.90-3.15, 2.05-2.45; MS (ESI) m/z 357, 355.

Example 132

[0557] Preparation of6-[3-(4-fluorophenoxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-6(1H)-yl]propylether maleate

[0558] Following Example 130, but starting with 4-fluorophenol andmaking non-critical variations, the title compound was obtained: ¹H NMR(300 MHz, CDCl₃) δ7.40-7.50, 6.90-7.30, 6.85-6.95, 4.32, 3.81,2.85-3.15, 2.10-2.25, 1.83; MS (ESI) m/z 339 (M⁺).

Example 133

[0559] Preparation of10-bromo-6-(2-phenoxyethyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indoleoxalate

[0560] Starting with3-tert-butyloxycarbonyl-10-bromo-1,2,3,4,5,6-tetrahydroazepino[4,5-b]indole,and β-bromophenetole, the title compound was obtained: ¹H NMR (300 MHz,CDCl₃) δ7.20-7.35, 6.90-7.10, 6.75-6.90, 4.49, 4.18, 3.40-3.65,3.00-3.30; MS (ESI) m/z 387, 385.

Example 134

[0561] Preparation of6-(2-phenoxyethyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole oxalate

[0562] Hydrogenolysis of10-bromo-6-(2-phenoxyethyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indoleoxalate gave the title compound: ¹H NMR (300 MHz, CDCl₃) δ6.70-7.35,4.40-4.55, 4.10-4.25, 3.45-3.55, 3.00-3.20; MS (ESI) m/z 307 (M⁺).

[0563] Preparation 22

[0564] Preparation of tert-butyl10-bromo-6-(2-ethoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0565] Prepared according to the procedure used to prepare tert-butyl6-(2-ethoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylatein 82% yield. ¹H NMR (300 MHz, CDCl₃) δ1.28, 1.50,2.90-2.99, 3.54-3.63,3.66-3.82, 4.22, 4.79, 6.98, 7.12, 7.27; MS (ESI+) for C₂₁H₂₇BrN₂O₄ m/z451.1 (M+H)⁺.

[0566] Preparation 23

[0567] Preparation of(3-(tert-butoxycarbonyl)-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)aceticacid

[0568] tert-Butyl6-(2-ethoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.606 g, 1.63 mmol) is dissolved in MeOH (20 mL) and 1N NaOH (2.44 mL,2.44 mmol, 1.5 equiv.) is added. The resulting solution is stirred at rtfor 3 h. The reaction mixture is concentrated and the residue ispartitioned between EtOAc (50 mL) and 10% aqueous citric acid (30 mL).The layers are separated and the aqueous layer is extracted with EtOAc(25 mL). The combined organic layers are washed with water (2×15 mL) andbrine (15 mL), dried over MgSO₄, filtered and concentrated. Crude(3-(tert-butoxycarbonyl)-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)aceticacid (0.566 g) is obtained in quantitative yield. ¹H NMR (300 MHz,CDCl₃) δ1.49, 2.92-2.96, 3.00-3.04, 3.67-3.79, 4.83, 7.14, 7.19-7.20,7.49; MS (ESI−) for C₁₉H₂₄N₂O₄ m/z 343.1 (M−H)⁻.

[0569] Preparation 24

[0570] Preparation of(10-bromo-3-(tert-butoxycarbonyl)-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)aceticacid

[0571] Prepared according to the procedure used to prepare(3-(tert-butoxycarbonyl)-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)aceticacid.

[0572] Preparation 25

[0573] Preparation of tert-butyl6-[2-(2,3-dimethylanilino)-2-oxoethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0574](3-(tert-butoxycarbonyl)-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)aceticacid (3.38 mmol) was dissolved in THF (20 mL) and 2,3-dimethylaniline(0.43 mL, 0.43 g, 3.6 mmol, 1.05 equiv.), dimethylaminopyridine (0.415g, 3.40 mmol, 1.01 equiv.), and diisopropylcarbodiimide (0.60 mL, 0.48g, 3.8 mmol, 1.13 equiv.) were added. The reaction mixture was stirredat rt under N₂ for 18 h. The reaction mixture was taken up in EtOAc (100mL) and this solution was washed with 10% aqueous citric acid (2×50 mL),5% aqueous NaHCO₃ (2×50 mL), and brine (50 mL). The organic layer wasdried over MgSO₄, filtered, and concentrated. The crude product (1.7223g) was chromatographed (SiO₂ 187 g, eluted with 10:1 toluene:acetonefollowed by 9:1 toluene:acetone) to give tert-butyl6-[2-(2,3-dimethylanilino)-2-oxoethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(1.1066 g) in 67% yield. ¹H NMR (300 MHz, CD₃OD) δ1.50, 2.01-2.03, 2.27,2.29-3.12, 3.66-3.75, 3.75-3.83, 5.03, 7.04-7.19, 7.37, 7.49; MS (ESI+)for C₂₇H₃₃N₃O₃ m/z 448.1 (M+H)⁺.

Example 135

[0575] Preparation ofN-(2,3-dimethylphenyl)-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamidehydrochloride

[0576] tert-Butyl6-[2-(2,3-dimethylanilino)-2-oxoethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(1.02 g, 2.27 mmol) was disolved in CH₂Cl₂ (15 mL), then trifluoroaceticacid (3.0 mL, 4.44 g, 38.9 mmol, 17.2 equiv.) was added. The resultingsolution was stirred at rt for 1.5 h. The reaction mixture wasconcentrated to dryness, then the residue was partitioned between EtOAc(100 mL) and 1N NaOH (50 mL). The layers were separated, and the aqueouslayer was extracted with EtOAc (50 mL). The combined organic layers werewashed with brine (25 mL), dried over MgSO₄, filtered, and concentrated.The residue was combined with EtOAc (20 mL) and 1M HCl in Et₂O (20 mL),then the salt was collected by filtration. The salt was dried undervacuum over P₂O₅.N-(2,3-dimethylphenyl)-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetanidehydrochloride (0.7739 g) was obtained in 89% yield. ¹H NMR (300 MHz,CD₃OD) δ2.11, 2.29, 3.23-3.26, 3.32-3.35, 3.47-3.56, 5.12, 7.06-7.15,7.22, 7.44, 7.53; MS (ESI+) for C₂₂H₂₅N₃O m/z 348.3 (M+H)⁺.

[0577] Preparation 26

[0578] Preparation of tert-butyl6-[2-oxo-2-(3-toluidino)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0579] Prepared according to the procedure used to prepare tert-butyl6-[2-(2,3-dimethylanilino)-2-oxoethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylatein 92% yield. ¹H NMR (300 MHz, CD₃OD) δ1.50-1.51, 2.31, 3.00-3.06,3.69-3.80, 4.98, 6.95, 7.06, 7.13, 7.19, 7.30, 7.34, 7.38, 7.47; MS(ESI+) for C₂₆H₃₁N₃O₃ m/z 434.1 (M+H)⁺.

Example 136

[0580] Preparation ofN-(3-methylphenyl)-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamidehydrochloride

[0581] Prepared according to the procedure used to prepareN-(2,3-dimethylphenyl)-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamidehydrochloride in 91% yield. ¹H NMR (300 MHz, DMF) δ2.47, 3.46-3.51,3.63-3.68, 3.73-3.83, 5.41, 7.08-7.11, 7.25, 7.33, 7.39, 7.66-7.75; MS(ESI+) for C₂₁H₂₃N₃O m/z 334.2 (M+H)⁺.

[0582] Preparation 27

[0583] Preparation of tert-butyl6-[2-(2-fluoro-4-methylanilino)-2-oxoethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0584] Prepared according to the procedure used to prepare tert-butyl6-[2-(2,3-dimethylanilino)-2-oxoethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylatein 77% yield. ¹H NMR (300 MHz, CDCl₃) δ1.50, 2.29, 2.97-3.10, 3.71-3.81,4.89, 6.80, 6.92, 7.03, 7.20, 7.23-7.30, 7.55-7.59, 7.97; MS (ESI+) forC₂₆H₃₀FN₃O₃ m/z 452.1 (M+H)⁺

Example 137

[0585] Preparation ofN-(2-fluoro-4-methylphenyl)-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamidehydrochloride

[0586] Prepared according to the procedure used to prepareN-(2,3-dimethylphenyl)-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamidehydrochloride in 88% yield. ¹H NMR (300 MHz, DMF) δ2.48, 3.48-3.51,3.62-3.68, 3.69-3.81, 5.51, 7.17, 7.24-7.36, 7.72, 7.73, 8.04; MS (ESI+)for C₂₁H₂₂FN₃O m/z 352.1 (M+H)⁺.

[0587] Preparation 28

[0588] Preparation of tert-butyl6-[2-(mesitylamino)-2-oxoethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0589] Prepared according to the procedure used to prepare tert-butyl6-[2-(2,3-dimethylanilino)-2-oxoethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylatein 76% yield. ¹H NMR (300 MHz, CDCl₃) δ1.50, 2.01, 2.23, 3.03-3.12,3.70-3.85, 4.93, 6.36, 6.83, 7.20, 7.28, 7.34, 7.53-7.57; MS (ESI+) forC₂₈H₃₅N₃O₃ m/z 462.1 (M+H)⁺.

Example 138

[0590] Preparation ofN-mesityl-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamidehydrochloride

[0591] Prepared according to the procedure used to prepareN-(2,3-dimethylphenyl)-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamidehydrochloride in 99% yield. ¹H NMR (300 MHz, DMF) δ2.18, 2.23,3.29-3.33, 3.49-3.66, 5.28, 6.89, 7.10, 7.20, 7.55, 7.62; MS (ESI+) forC₂₃H₂₇N₃O m/z 362.2 (M+H)⁺.

[0592] Preparation 29

[0593] Preparation of tert-butyl6-[2-(4-methoxyanilino)-2-oxoethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0594] Prepared according to the procedure used to prepare tert-butyl6-[2-(2,3-dimethylanilino)-2-oxoethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylatein 86% yield. ¹H NMR (300 MHz, CDCl₃) δ1.49, 2.96-3.11, 3.71-3.81, 4.85,6.81, 6.86, 7.21, 7.21-7.31, 7.57; MS (ESI+) for C₂₆H₃₁N₃O₄ m/z 450.1(M+H)⁺.

Example 139

[0595] Preparation ofN-(4-methoxyphenyl)-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamidehydrochloride

[0596] Prepared according to the procedure used to prepareN-(2,3-dimethylphenyl)-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamidehydrochloride in 96% yield. ¹H NMR (300 MHz, CD₃OD) δ3.23-3.30,3.48-3.56, 3.78, 5.05, 6.89, 7.11, 7.19, 7.37, 7.45, 7.52; MS (ESI+) forC₂₁H₂₃N₃O₂ m/z 350.1 (M+H)⁺.

[0597] Preparation 30

[0598] Preparation of tert-butyl6-(2-anilino-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0599] Prepared according to the procedure used to prepare tert-butyl6-[2-(2,3-dimethylanilino)-2-oxoethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate.¹H NMR (300 MHz, CDCl₃) δ1.46, 2.99, 3.06, 3.71-3.77, 4.84, 7.01, 7.09,7.17-7.31, 7.55; MS (ESI+) for C₂₅H₂₉N₃O₃ m/z 420.1 (M+H)⁺.

Example 140

[0600] Preparation ofN-phenyl-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamidetrifluoroacetate

[0601] Prepared according to a procedure closely related to that used toprepareN-(2,3-dimethylphenyl)-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamidehydrochloride of Example 135. ¹H NMR (300 MHz, CD₃OD) δ3.21-3.27,3.46-3.54, 5.06, 7.09, 7.10, 7.17, 7.28-7.35, 7.50, 7.54, 7.54; MS(ESI+) for C₂₀H₂₁N₃O m/z 320.2 (M+H)⁺.

Example 141

[0602] Preparation ofN-(4-fluorophenyl)-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamidehydrochloride

[0603] Prepared according to the procedure used to prepareN-(2,3-dimethylphenyl)-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamidehydrochloride of Example 135. ¹H NMR (300 MHz, CD₃OD) δ3.20-3.29,3.44-3.52, 5.05, 7.04, 7.08, 7.16, 7.34, 7.49, 7.56; MS (ESI+) forC₂₀H₂₀FN₃O m/z 338.1 (M+H)⁺.

Example 142

[0604] Preparation ofN-(3-nitrophenyl)-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamidehydrochloride

[0605] Prepared according to the procedure used to prepareN-(2,3-dimethylphenyl)-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamidehydrochloride of Example 135. ¹H NMR (300 MHz, CD₃OD)δ3.22-3.30,3.47-3.55, 5.11, 7.10, 7.17, 7.34, 7.51, 7.57, 7.88, 7.98,8.64; MS (ESI+) for C₂₀H₂₀N₄O₃ m/z 365.1 (M+H)⁺.

Example 143

[0606] Preparation ofN-(3-methoxyphenyl)-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamidehydrochloride

[0607] Prepared according to the procedure used to prepareN-(2,3-dimethylphenyl)-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamidehydrochloride of Example 135. ¹H NMR (300 MHz, CD₃OD) δ3.19-3.28,3.42-3.51, 3.75, 5.06, 6.68, 7.09, 7.11, 7.17, 7.21, 7.30, 7.36, 7.50;MS (ESI+) for C₂₁H₂₃N₃O₂ m/z 350.3 (M+H)⁺.

Example 144

[0608] Preparation ofN-(4-cyanophenyl)-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamidehydrochloride

[0609] Prepared according to the procedure used to prepareN-(2,3-dimethylphenyl)-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamidehydrochloride of Example 135. ¹H NMR (300 MHz, CD₃OD) δ3.22-3.30,3.46-3.53, 5.13, 7.10, 7.17, 7.35, 7.51, 7.66, 7.80; MS (ESI+) forC₂₁H₂₀N₄O m/z 345.2 (M+H)⁺.

Example 145

[0610] Preparation ofN-(3,5-dimethoxyphenyl)-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamidehydrochloride

[0611] Prepared according to the procedure used to prepareN-(2,3-dimethylphenyl)-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamidehydrochloride of Example 135. ¹H NMR (300 MHz, CD₃OD) δ3.19-3.28,3.43-3.51, 3.73, 5.05, 6.26, 6.84, 7.09, 7.17, 7.35, 7.49; MS (ESI+) forC₂₂H₂₅N₃O₃ m/z 380.2 (M+H)⁺.

Example 146

[0612] Preparation of N-(2,4-dimethoxyphenyl)-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamidehydrochloride

[0613] Prepared according to the procedure used to prepareN-(2,3-dimethylphenyl)-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamidehydrochloride. ¹H NMR (300 MHz, CD₃OD) δ3.22-3.30, 3.45-3.52, 3.77,3.79, 5.09, 6.45, 6.57, 7.12, 7.21, 7.40, 7.53, 7.70; MS (ESI+) forC₂₂H₂₅N₃O₃ m/z 380.2 (M+H)⁺.

Example 147

[0614] Preparation ofN-(3-chloro-4-fluorophenyl)-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamidehydrochloride

[0615] Prepared according to the procedure used to prepareN-(2,3-dimethylphenyl)-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamidehydrochloride of Example 135. ¹H NMR (300 MHz, CD₃OD) δ3.23-3.31,3.47-3.55, 5.08, 7.10, 7.18, 7.21, 7.35, 7.46, 7.52, 7.86; MS (ESI+) forC₂₀H₁₉ClFN₃O m/z 372.0 (M+H)⁺.

Example 148

[0616] Preparation ofN-[2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethyl]aniline

[0617] tert-Butyl 6-(2-anilino-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.059 g, 0.14 mmol) was dissolved inTHF (5 mL) and LAH (0.0080 g, 0.21 mmol, 1.5 equiv.) was added. Thereaction mixture was refluxed for 6 h under N₂. The reaction mixture wasquenched with water and extracted with EtOAc. The extracts were treatedwith TFA, and the resulting mixture was concentrated. THF and excess LAHwere added and the reaction mixture was refluxed for 2 h. The reactionmixture was quenched by the addition of acetone, methanol, and water.The resulting mixture was extracted with EtOAc (4×) and the reactionmixture was concentrated. The crude product was purified by PTLC (1mm×20cm×20cm plate, developed with 10% MeOH:CH₂Cl₂, eluted with MeOH) toyield N-[2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethyl]aniline(0.0093 g) in 22% yield. ¹H NMR (400 MHz, CDCl₃) δ2.87-2.89, 2.93-2.96,3.03, 3.09, 3.49-3.53, 4.31, 6.57, 6.74, 7.07-7.28, 7.50.

[0618] Preparation 31

[0619] Preparation of tert-butyl6-(1H-benzimidazol-2-ylmethyl)-10-bromo-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0620] A solution of(10-bromo-3-(tert-butoxycarbonyl)-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)aceticacid (0.152 g, 0.359 mmol) and triethylamine (0.052 mL, 0.038 g, 0.372mmol, 1.04 equiv.) in THF (2 mL) was cooled to 0° C. under N₂. Isobutylchloroformate (0.048 mL, 0.051 g, 0.372 mmol, 1.04 equiv.) was added andthe reaction mixture was stirred for 2.3 h. o-Phenylenediamine (0.0406g, 0.375 mmol, 1.04 equiv.) and acetic acid (0.24 mL, 0.26 g, 4.25 mmol,11.8 equiv.) were added, and the reaction mixture was heated to 50° C.The temperature of the reaction mixture gradually was increased to 64 °C. over 3 h. After 19 h, the reaction mixture was cooled to rt. Thereaction mixture was taken up in EtOAc, and the resulting solution waswashed with water, saturated aq. NaHCO₃, and brine. The organic layerwas dried over MgSO₄, filtered and concentrated. The crude product(0.1865 g) was chromatographed (SiO₂ 22 g, eluted with 5:1toluene:acetone) to give tert-butyl6-(1H-benzimidazol-2-ylmethyl)-10-bromo-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.105 g) in 59% yield. ¹H NMR (300 MHz, CDCl₃) δ1.12, 3.20, 3.54,3.68-3.74, 5.54, 5.58, 6.88, 7.20, 7.23-7.30.

Example 149

[0621] Preparation of6-(1H-benzimidazol-2-ylmethyl)-10-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0622] tert-Butyl6-(1H-benzimidazol-2-ylmethyl)-10-bromo-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.105 g, 0.212 mmol) was dissolved in CH₂Cl₂ (5 mL) and trifluoroaceticacid (2.0 mL, 2.96 g, 26.0 mmol, 122 equiv.) was added. This mixture wasstirred at rt in a capped vessel for 2.5 h. The reaction mixture wasconcentrated to dryness. The residue was taken up in EtOAc (2 mL), and1M HCl in Et₂O was added. The hydrochloride salt was collected byfiltration and dried under vacuum.6-(1H-benzimidazol-2-ylmethyl)-10-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride (0.943 g) was produced in quantitative yield. ¹H NMR (300MHz, DMF) δ3.61-3.70, 3.83-3.86, 6.12, 7.06, 7.31, 7.36-7.42, 7.66-7.74,7.74; ¹H NMR (300 MHz, CD₃OD) δ3.33-3.36, 3.54-3.59, 3.83-3.86, 6.04,7.09, 7.35, 7.41, 7.54-7.57, 7.71-7.74; MS (ESI+) for C₂₀H₁₉BrN₄ m/z395, 396.9 (M+H)⁺.

[0623] Preparation 32

[0624] Preparation of tert-butyl10-bromo-6-(2-isobutoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0625] Obtained as a by-product in the formation of tert-butyl6-(1H-benzimidazol-2-ylmethyl)-10-bromo-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate.¹H NMR (300 MHz, CDCl₃) δ0.87, 1.50, 1.90, 2.93-2.99, 3.56-3.62,3.68-3.82, 3.93, 4.80, 6.98, 7.13, 7.27; MS (ESI+) for C₂₃H₃₁BrN₂O₄ m/z479 (M+H)⁺.

Example 150

[0626] Preparation of isobutyl(10-bromo-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetate

[0627] tert-butyl10-bromo-6-(2-isobutoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.0412 g, 0.0859 mmol) was dissolved in CH₂Cl₂ (2 mL) andtrifluoroacetic acid (1.0 mL, 1.48 g, 13.0 mmol, 151 equiv.) was added.The resulting solution was stirred at rt for 2.5 h. The reaction mixturewas concentrated to dryness. The residue was taken up in EtOAc (2 mL),then treated with 1N HCl in Et₂O. Hydrochloride salt formation did notoccur and the resulting solution were concentrated to dryness. Theresidue was partitioned between EtOAc and 1N NaOH. The layers wereseparated, and the aqueous layer was extracted with EtOAc. The combinedorganic layers were washed with brine, dried over MgSO₄, filtered andconcentrated. The crude isobutyl(10-bromo-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetate (0.0260g) was obtained in 80% yield. ¹H NMR (300 MHz, CD₃OD) δ0.85, 1.86,2.98-3.03, 3.11-3.14, 3.53-3.56, 3.91, 5.02, 6.94, 7.18, 7.25; MS (ESI+)for C₁₈H₂₃BrN₂O₂ m/z 379.0 (M+H)⁺.

Example 151

[0628] Preparation of2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-ylacetic acid hydrochloride

[0629] tert-Butyl6-(2-ethoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.122 g, 0.328 mmol) was dissolved in methanol (5 mL). Strongly acidiccation exchange resin (Bio-Rad AG 50W-2×200-400 mesh, 0.424 g) was addedand the reaction mixture was stirred overnight at rt. The resin wascollected by filtration, then washed with methanol. The resin wascombined with 1:1 7M aqueous NH₄OH and methanol, and the resin wasremoved by filtration. The filtrate was concentrated to dryness, and theresidue was taken up in methanol and concentrated to dryness to removeexcess NH₃. The free amino acid was treated with concentrated aqueousHCl (11.6 M, 3 drops) in methanol and the mixture was concentrated togive 2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-ylacetic acidhydrochloride (0.088 g)in 96% yield as a white solid. ¹H NMR (300 MHz,CD₃OD) δ3.21-3.25, 3.45-3.51, 5.05, 7.10, 7.18, 7.29, 7.50; MS (ESI−)for C₁₄H₁₆N₂O₃ m/z 243.1 (M−H)⁻.

[0630] Preparation 33

[0631] Preparation of tert-butyl6-[2-(dimethylamino)-2-oxoethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0632] tert-Butyl1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.100 g, 0.349mmol) was dissolved in DMF (1.0 mL) under N₂ at rt. NaH (0.0450 g, 1.13mmol, 3.22 equiv., 60% dispersion) was added and the mixture was stirredat rt for 30 min. 2-Chloro-N,N-dimethylacetamide (86 μL, 0.102 g, 0.838mmol, 2.4 equiv.) was added, and the reaction mixture was stirred at rtfor 24 h. The reaction mixture was poured over ice, thenextracted withEtOAc (2×). The organic extracts was washed first with water, then withbrine and dried over MgSO₄. The organic extracts was filtered andconcentrated to yield a crude product (0.148 g). The crude product waschromatographed (SiO₂ 18 g, eluted with 3:1 toluene:acetone) to givetert-butyl6-[2-(dimethylamino)-2-oxoethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.116 g) in 90% yield. ¹H NMR (300 MHz, CDCl₃) δ1.50, 2.87-2.95, 3.01,3.00-3.07, 3.13, 3.68-3.80, 4.85, 7.07-7.19, 7.47-7.51; MS (ESI+) forC₂₁H₂₉N₃O₃ m/z 372.2 (M+H)⁺.

Example 152

[0633] Preparation ofN,N-dimethyl-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamidehydrochloride

[0634] tert-Butyl6-[2-(dimethylamino)-2-oxoethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.113 g, 0.305 mmol) was dissolved in CH₂Cl₂ (3 mL) at rt. CF₃CO₂H (1mL) was added and the reaction mixture was stirred for 40 min. Thereaction mixture was concentrated to give a crude product (0.145 g). Thecrude product was dissolved in EtOAc (3 mL), then 1 N HCl in Et₂O (6 mL)was added and the precipitated salt was collected by filtration.N,N-Dimethyl-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamidehydrochloride (0.0896 g) was obtained in 95% yield. ¹H NMR (300 MHz,CD₃OD) δ2.99, 3.14-3.17, 3.21-3.24, 3.26, 3.47-3.50, 5.16, 7.08, 7.15,7.30, 7.50; MS (ESI+) for C₁₆H₂₁N₃O m/z 272.2 (M+H)⁺.

[0635] Preparation 34

[0636] Preparation of tert-butyl6-(2-amino-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylatetert-Butyl 1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.0994 g, 0.347) and iodoacetamide (0.0704 g, 0.381 mmol, 1.10 equiv.)was dissolved in DMF (1 mL) at rt under N₂. NaH (0.033 g, 0.825 mmol,2.38 equiv., 60% dispersion) was added, and the reaction mixture wasstirred for 16 h. Additional NaH (0.039 g) was added and the reactionmixture was stirred for 1.5 h. The reaction mixture was poured over ice,and the resulting mixture was extracted with EtOAc. The organic extractswas washed with water and then with brine. The organic extracts wasdried over MgSO₄, filtered, and concentrated. The crude product (0.124g) was purified by PTLC (2×1 mm×20 cm×20 cm SiO₂ plates, developed with3:1 EtOAc:hexane, eluted with 10% MeOH in CH₂Cl₂) to give tert-butyl6-(2-amino-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.0233 g) in 19% yield. ¹H NMR (300 MHz, CDCl₃) δ1.50, 2.93-3.07,3.68-3.79, 4.71, 5.33, 5.90-5.94, 7.15-7.24, 7.50-7.54; MS (ESI+) forC₁₉H₂₅N₃O₃ m/z 344.1 (M+H)⁺.

Example 153

[0637] Preparation of2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamidehydrochloride

[0638] tert-Butyl6-(2-amino-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.0233 g, 0.0678 mmol) was dissolved in CH₂Cl₂ (2 mL) at rt. CF₃CO₂H(0.8 mL) was added, then the reaction mixture was stirred for 30 min.The reaction mixture was concentrated to give a crude product (0.0288g). The crude product was dissolved in EtOAc (1 mL), 1 N HCl in Et₂O (2mL) was added, and the precipitated salt was collected by filtration.2-(2,3,4,5-Tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamidehydrochloride (0.0151 g) was obtained in 80% yield. ¹H NMR (300 MHz,DMF-d₇) δ3.29-3.33, 3.40-3.43, 3.50-3.58, 4.97, 7.07, 7.15, 7.45, 7.53;MS (ESI+) for C₁₄H₁₇N₃O m/z 244.1 (M+H)⁺.

[0639] Preparation 35

[0640] Preparation of tert-butyl6-[2-(phenylsulfinyl)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0641] tert-Butyl1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.170 g, 0.594mmol) and 2-chloroethyl phenyl sulfoxide (0.225 g, 1.20 mmol, 2.0equiv.) was dissolved in DMF (10 mL) at rt. NaH (0.100 mg, 2.5 mmol,4.21 equiv., 60% dispersion) was added, then the reaction mixture wasstirred for 3 h. The reaction was quenched with a saturated aqueousNH₄Cl solution and partitioned between water and CH₂C₂. The aqueouslayer was extracted with CH₂Cl₂ (3×). The combined organic layers wereconcentrated and the residue was dissolved in EtOAc, dried over MgSO₄,filtered, and concentrated. The crude product was chromatographed(Biotage 12 m SiO₂ column, eluted with a 20% to 30% EtOAc in hexanegradient) to give tert-butyl6-[2-(phenylsulfinyl)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate.

Example 154

[0642] Preparation of6-[2-(phenylsulfinyl)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0643] tert-Butyl6-[2-(phenylsulfinyl)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylatewas dissolved in trifluoroacetic acid and stirred for 5 min. Thereaction mixture was concentrated to dryness, and the residue wasdissolved in 10% aqueous acetic acid. This aqueous solution wasextracted with CH₂Cl₂ (3×). The aqueous layer was adjusted to pH 10 withNaOH, then extracted with EtOAc (3×). The combined EtOAc extracts wasdried over MgSO₄, filtered, and concentrated. The product waschromatographed (SiO₂, 10% methanol in CH₂Cl₂) to give6-[2-(phenylsulfinyl)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(0.116 g) in 70% yield as a white solid. ¹H NMR (300 MHz, CD₃OD)δ3.09-3.24, 3.28-3.44, 4.40, 4.62, 7.05, 7.13, 7.25, 7.43, 7.50-7.59;¹³C NMR (75 MHz, CD₃OD) δ22.79, 24.84, 37.04, 46.77, 48.66, 56.93,110.42, 112.81, 116.30, 118.82, 120.17, 120.93, 122.91, 125.18, 128.93,130.72, 132.72, 136.17, 136.92, 143.37.

[0644] Preparation 36

[0645] Preparation of tert-butyl6-[2-(phenylsulfonyl)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0646] tert-Butyl1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.111 g, 0.388mmol) was dissolved in CH₂Cl₂ (10 mmol) and this solution was added to amixture of 50% aqueous KOH (5 mL) and tetrabutylammonium hydrogensulfate (0.100 g). The biphasic mixture was stirred vigorously at rt.2-Chloroethyl phenyl sulfone (0.318 g, 1.55 mmol) was added, then thereaction mixture was stirred for 4 h. The organic phase was separatedand the aqueous phase was extracted with CH₂Cl₂. The combined organiclayers was concentrated. The crude product was chromatographed (Biotage40s SiO₂ column, eluted with a 10% to 40% EtOAc in hexane gradient) togive tert-butyl6-[2-(phenylsulfonyl)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.154 g) in 87% as a clear solid. ¹H NMR (300 MHz, CDCl₃) δ1.48,2.87-2.93, 3.38-3.42, 3.63, 3.69, 4.52, 7.04-7.17, 7.42, 7.53-7.59,7.63-7.70, 7.88.

Example 155

[0647] Preparation of6-[2-(phenylsulfonyl)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[0648] tert-Butyl6-[2-(phenylsulfonyl)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.139 g, 0.306 mmol) was treated with trifluoroacetic acid (1 mL) for 5min. CH₂Cl₂ was added and the reaction mixture was concentrated todryness. The salt was partitioned between CH₂Cl₂ and a mixture of 1M KOHand brine. The organic layer was dried over MgSO₄, filtered andconcentrated. The crude product was chromatographed (SiO₂, eluted with1:1 EtOAc:hexane) to give6-[2-(phenylsulfonyl)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(0.0123 g) as a white solid. ¹H NMR (300 MHz, CD₃OD) δ3.13, 3.29-3.33,3.42, 3.50, 3.71, 4.65, 7.07, 7.14, 7.22, 7.42, 7.51, 7.66, 7.70.

[0649] Preparation 37

[0650] Preparation of tert-butyl6-(2-hydroxyethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0651] tert-Butyl6-(2-ethoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.602 g, 1.62 mmol) was dissolved in THF (15 mL), and the resultingsolution was cooled to -10° C. under N₂. LiBH₄ (0.0756 g, 3.47 mmol,2.14 equiv.) was added and the reaction mixture was allowed to warm tort. After 19.5 h, the reaction mixture was cooled to 0° C., and LiBH₄(0.0250 g, 1.15 mmol, 0.71 equiv.) was added and the reaction mixturewas allowed to warm up for 3.5 h. The reaction mixture was combined withwater and was extracted with EtOAc (2×). The combined organic layers waswashed with brine, dried over MgSO₄, filtered, and concentrated to givetert-butyl6-(2-hydroxyethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.533 g) in acceptable purity and essentially quantitative yield. ¹HNMR (300 MHz, CD₃OD) δ1.48-1.51, 3.00-3.11, 3.66-3.79, 3.87-3.95, 4.27,7.12, 7.19, 7.32, 7.50; MS (ESI+) for C₁₉H₂₆N₂O₃ m/z 331.2 (M+H)⁺.

Example 156

[0652] Preparation of2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethanol hydrochloride

[0653] 2-(2,3,4,5-Tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethanolhydrochloride was prepared from tert-butyl6-(2-hydroxyethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylateby the procedure used to prepare2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-ylacetic acid hydrochloridein 48% yield. ¹H NMR (300 MHz, CDCl₃) δ3.22, 3.37, 3.44-3.52, 3.80,4.30, 7.07, 7.15, 7.37, 7.48; MS (ESI+) for C₁₄H₁₈N₂O m/z 231.3 (M+H)⁺.

[0654] Preparation 38

[0655] Preparation of tert-butyl6-[2-(4-chlorophenoxy)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0656] tert-Butyl6-(2-hydroxyethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.533 g, 1.61 mmol), p-chlorophenol (0.224 g, 1.74 mmol, 1.08 equiv.)and triphenylphosphine (0.445 g, 1.70 mmol, 1.05 equiv.) was dissolvedin THF (10 mL) and stirred at rt under N₂. Diethyl azodicarboxylate(0.30 mL, 0.337 g, 1.93 mmol, 1.2 equiv.) was added, and the reactionmixture was stirred for 2.5 h. The reaction mixture was concentrated togive crude product (1.85 g), which was chromatographed (SiO₂ 175 g,eluted with 4:1 hexane:EtOAc) to give tert-butyl6-[2-(4-chlorophenoxy)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.622 g) in 88% yield. ¹H NMR (300 MHz, CD₃OD) δ1.48, 2.96-3.03,3.05-3.14, 3.63-3.78, 4.15, 4.48, 6.70, 7.11, 7.15-7.20, 7.17,7.27-7.31, 7.46-7.51; MS (ESI+) for C₂₅H₂₉ClN₂O₃ m/z 440.9 (M+H)⁺.

Example 157

[0657] Preparation of 4-chlorophenyl2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethyl etherhydrochloride

[0658] tert-Butyl6-[2-(4-chlorophenoxy)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.622 g, 1.41 mmol) was dissolved in CH₂Cl₂ (10 mL) at rt. CF₃CO₂H (4mL) was added, then the reaction mixture was stirred for 1 h. Thereaction mixture was concentrated and the residue was taken up in EtOAcand washed with 1 N NaOH. The aqueous layer was extracted with EtOAc,and the combined organic layers were washed with brine, dried overMgSO₄, filtered, and concentrated. The crude product (0.541 g) wasdissolved in EtOAc (2 mL) and 1 N HCl in Et₂O (2 mL) was added. Thesolvents were removed under vacuum and Et₂O (10 mL) was added to theresidue. The resulting mixture was sonicated and the finely powderedsalt was collected by filtration. 4-Chlorophenyl2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethyl etherhydrochloride (0.503 g) was obtained in 94% yield. ¹ H NMR (300 MHz,CD₃OD) δ3.16-3.20, 3.35-3.50, 4.22, 4.59, 6.76, 7.07, 7.18, 7.18, 7.43,7.48; MS (ESI+) for C₂₀H₂₁ClN₂O m/z 341.0 (M+H)⁺.

Example 158

[0659] Preparation of 4-fluorophenyl2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethyl etherhydrochloride

[0660] Prepared according to the procedure used to prepare4-chlorophenyl 2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethylether hydrochloride of Example 157. ¹H NMR (300 MHz, CD₃OD) δ3.17-3.21,3.39-3.50, 4.18, 4.56, 6.75, 6.92, 7.08, 7.18, 7.42, 7.48; MS (ESI+) forC₂₀H₂₁FN₂O m/z 325.1 (M+H)⁺.

[0661] Preparation 39

[0662] Preparation of tert-butyl6-{2-[(methylsulfonyl)oxy]ethyl}-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0663] tert-Butyl6-(2-hydroxyethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.181 g, 0.549 mmol) and triethylamine (0.115 mL, 0.0833 g, 0.824 mmol,1.5 equiv.) were dissolved in CH₂Cl₂ at -10° C. under N₂. MsCl (0.0510mL, 0.0755g, 0.659 mmol, 1.2 equiv.) was added and the reaction mixturewas stirred for 30 min. The reaction mixture was taken up in EtOAc (25mL) and was washed sequentially with 10% citric acid (10 mL), 5% NaHCO₃(10 mL), and brine (10 mL). The organic layer was dried over MgSO₄,filtered, and concentrated. The crude tert-butyl6-{2-[(methylsulfonyl)oxy]ethyl}-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylatewas used directly in the next reaction.

[0664] Preparation 40

[0665] Preparation of tert-butyl6-[2-(phenylsulfanyl)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0666] tert-Butyl6-(2-hydroxyethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate,(0.0488 g, 0.148 mmol) was dissolved in CH₂Cl₂ (5 mL) and stirred at rt.Triethylamine (5 mL) was added, followed by methanesulfonyl chloride(0.017 mL, 0.221 mmol, 1.50 equiv.). The reaction mixture was stirredfor 2 h, and additional methanesulfonyl chloride (0.015 mL) was added.After 30 min, a mixture of thiophenol (0.065 mL, 0.592 mmol, 4.0 equiv.)and KOH (12 equiv.) in DMF (5 mL) was added, and the resulting mixturewas stirred for 30 min. The reaction mixture was quenched with saturatedaqueous NH₄Cl, then the resulting mixture was extracted with CH₂Cl₂(3×). The combined organic extracts were dried over MgSO₄, filtered, andconcentrated. The crude product was purified by PTLC (1 mm×20 cm×20 cmSiO₂ plates, developed with 1:4 EtOAc:hexane) to give tert-butyl6-[2-(phenylsulfanyl)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.017 g) in 28% yield as a white solid. ¹H NMR (300 MHz, CDCl₃) δ1.52,2.92, 2.99, 3.17, 3.66-3.73, 4.28, 7.10-7.20, 7.25-7.41, 7.48; MS (ESI+)for C₂₅H₃₀N₂O₂S m/z 423 (M+H)⁺.

Example 159

[0667] Preparation of phenyl2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethyl sulfidetrifluoroacetate

[0668] tert-Butyl6-[2-(phenylsulfanyl)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.0532 g, 0126 mmol) was dissolved in trifluoroacetic acid (2 mL), andthe solution was stirred for 5 min. The reaction mixture wasconcentrated to dryness to give phenyl2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethyl sulfidetrifluoroacetate (0.70 g) as a tan solid. ¹H NMR (300 MHz, CD₃OD) δ3.12,3.18, 3.30, 3.34-3.41, 4.41, 7.08, 7.15, 7.17-7.26, 7.45; MS (ESI+) forC₂₀H₂₂N₂S m/z 323.2 (M+H)⁺.

[0669] Preparation 41

[0670] Preparation of tert-butyl6-(2-azidoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0671] tert-Butyl6-{2-[(methylsulfonyl)oxy]ethyl}-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.224 g, 0.549 mmol) and NaN₃ (0.357 g, 5.49 mmol, 10.0 equiv.) weredissolved in DMF (2.5 mL) and the solution was stirred at 60° C. underN₂ for 14.5 h. The reaction mixture was taken up in EtOAc and washedwith water (2×15 mL). The aqueous layers were back extracted with EtOAc(25 mL). The combined organic layers were washed with brine (10 mL),dried over MgSO₄, filtered and concentrated. The crude product (0.214 g)was chromatographed (SiO₂ 25 g, eluted with 3:1 hexane:EtOAc) to givetert-butyl6-(2-azidoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.184 g) in 94% yield. ¹H NMR (300 MHz, CDCl₃) δ1.51, 2.99-3.10, 3.60,3.66-3.84, 4.26, 7.14, 7.21, 7.27, 7.51; MS (ESI+) for C₁₉H₂₅N₅O₂ m/z356.2 (M+H)⁺.

[0672] Preparation 42

[0673] Preparation of tert-butyl6-(2-aminoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0674] tert-Butyl6-(2-azidoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.174 g, 0.490 mmol) was dissolved in 1:1 EtOAc:EtOH (4 mL). 10% Pd/C(0.0543 g) was added, then the reaction mixture was stirred at rt underH₂ for 2 h. The reaction mixture was filtered through celite and thecelite pad was carefully washed with EtOAc. The filtrate wasconcentrated to give tert-butyl6-(2-aminoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.153 g) in 95% crude yield. ¹H NMR (300 MHz, CDCl₃) δ1.51, 2.99-3.10,3.67-3.80, 4.17, 7.12, 7.19, 7.32, 7.50.

Example 160

[0675] Preparation of2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethanaminedihydrochloride

[0676] tert-Butyl6-(2-aminoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.0336 g, 0.102 mmol) was dissolved in CH₂Cl₂ (2 mL) at rt. CF₃CO₂H (1mL) was added and the reaction mixture was stirred for 4 h. The reactionmixture was concentrated and the residue was taken up in EtOAc (2 mL).HCl in Et₂O (1 N) and MeOH were added and the mixture was concentratedto give crude2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethanaminedihydrochloride (0.0339 g). ¹H NMR (300 MHz, DMF-d₇) δ3.48-3.51,3.53-3.59, 3.65-3.70, 3.75-3.79, 4.94, 7.27, 7.35, 7.72, 7.91; MS (ESI+)for C₁₄H₁₉N₃ m/z 230.2 (M+H)⁺.

[0677] Preparation 43

[0678] Preparation of tert-butyl6-{2-[(anilinocarbonyl)amino]ethyl}-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0679] tert-Butyl6-(2-aminoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.0399 g, 0.121 mmol) was dissolved in THF (2 mL) at rt under N₂.Phenyl isocyanate (0.016 g mL, 0.0173 g, 0.145 mmol, 1.20equiv.) wasadded, then the reaction mixture was stirred for 2.5 h. The reactionmixture was concentrated and the crude product (0.0598 g) waschromatographed (SiO₂ 25 g, eluted with 3:2 hexane:EtOAc) to givetert-butyl6-{2-[(anilinocarbonyl)amino]ethyl}-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.0390 g) in 72% yield. ¹H NMR (300 MHz, CDCl₃) δ1.36, 1.44, 2.96-3.08,3.42-3.51, 3.65-3.72, 4.17, 4.23, 5.14, 5.23, 6.94-7.30, 7.43-7.49; MS(ESI+) for C₂₆H₃₂N₄O₃ m/z 449.1 (M+H)⁺.

Example 161

[0680] Preparation ofN-phenyl-N′-[2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethyl]ureahydrochloride

[0681] tert-Butyl6-{2-[(anilinocarbonyl)amino]ethyl}-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.0390 g, 0.0869 mmol) was dissolved in CH₂Cl₂ (2 mL) at rt. CF₃CO₂H (1mL) was added, then the reaction mixture was stirred for 45 min. Thereaction mixture was concentrated and the residue was taken up in EtOAc(2 mL). 1 N HCl in Et₂O (2 mL) was added and the precipitated salt wascollected by filtration.N-Phenyl-N′-[2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethyl]ureahydrochloride (0.0296 g) was obtained in 88% yield. ¹H NMR (300 MHz,CD₃OD) δ3.19-3.22, 3.35-3.38, 3.43-3.53, 4.35, 6.97-7.03, 7.07, 7.17,7.25-7.27, 7.44, 7.48; MS (ESI+) for C₂₁H₂₄N₄O m/z 349.2 (M+H)⁺.

[0682] Preparation 44

[0683] Preparation of tert-butyl6-[2-(benzoylamino)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0684] tert-Butyl6-(2-aminoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.0401 g, 0.122 mmol) was dissolved in THF (2 mL) at rt under N₂.Diisopropylethylamine (0.028 mL, 0.0205 g, 0.158 mmol, 1.30 equiv.) andbenzoyl chloride (0.017 mL, 0.0205 g, 0.146 mmol, 1.20 equiv.) wereadded, then the reaction mixture was stirred for 19 h. Citric acid (10%)was added and the reaction mixture was stirred for 15 min. The reactionmixture was extracted with EtOAc and the organic layer was washedsequentially with 10% citric acid, saturated aqueous NaHCO₃, and brine.The organic layer was dried over MgSO₄, filtered and concentrated. Thecrude product (0.056 g) was chromatographed (SiO₂ 25 g, eluted with 1:1hexane:EtOAc) to give tert-butyl6-[2-(benzoylamino)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.0398 g) in 75% yield. ¹H NMR (300 MHz, CDCl₃) δ1.45, 1.48, 2.96-3.05,3.60-3.70, 3.74, 4.36-4.42, 6.29, 7.10-7.19, 7.31-7.43, 7.46-7.53, 7.63;MS (ESI+) for C₂₆H₃₁N₃O₃ m/z 434.1 (M+H)⁺.

Example 162

[0685] Preparation ofN-[2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethyl]benzamidehydrochloride

[0686] tert-Butyl6-[2-(benzoylamino)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.0398 g, 0.0918 mmol) was dissolved in CH₂Cl₂ (2 mL) at rt. CF₃CO₂H (1mL) was added, then the reaction mixture was stirred for 2 h. Thereaction mixture was concentrated and the residue was taken up in EtOAc(2 mL). HCl (1N) in Et₂O (2 mL) was added and the precipitated salt wascollected by filtration.N-[2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethyl]benzamidehydrochloride (0.0271 g) was obtained in 79% yield. ¹H NMR (300 MHz,CD₃OD) δ3.18-3.21, 3.33-3.38, 3.42-3.49, 3.69, 4.44, 7.05, 7.15,7.38-7.54, 7.60, 7.60, 8.55-8.59; MS (ESI+) for C₂₁H₂₃N₃O m/z 334.2(M+H)⁺.

[0687] Preparation 45

[0688] Preparation of tert-butyl6-{2-[(phenylsulfonyl)amino]ethyl}-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0689] tert-Butyl6-(2-aminoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.0403 g, 0.122 mmol) was dissolved in THF (2 mL) at rt under N₂.Diisopropylethylamine (0.043 mL, 0.0316 g, 0.245 mmol, 2.00 equiv.) andbenzenesulfonyl chloride (0.023 mL, 0.0324 g, 0.183 mmol, 1.50 equiv.)were added, then the reaction mixture was stirred for 19 h. Citric acid(10%) was added and the reaction mixture was stirred for 15 min. Thereaction mixture was extracted with EtOAc, and the organic layer waswashed sequentially with 10% citric acid, saturated aqueous NaHCO₃ andbrine. The organic layer was dried over MgSO₄, filtered, andconcentrated. The crude product (0.0649 g) was chromatographed (SiO₂ 25g, eluted with 2:1 hexane:EtOAc) to give tert-butyl6-{2-[(phenylsulfonyl)amino]ethyl}-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.0430 g) in 75% yield. ¹H NMR (300 MHz, CDCl₃) δ1.46, 1.52, 2.95-3.02,3.22-3.30, 3.63-3.75, 4.24-4.31, 4.63, 4.79, 7.09-7.26, 7.45-7.51, 7.48,7.58, 7.79; MS (ESI+) for C₂₅H₃₁N₃O₄S m/z 470.0 (M+H)⁺.

Example 163

[0690] Preparation ofN-[2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethyl]benzenesulfonamidehydrochloride

[0691] tert-Butyl6-{2-[(phenylsulfonyl)amino]ethyl}-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.0430 g, 0.0916 mmol) was dissolved in CH₂Cl₂ (2 mL) at rt. CF₃CO₂H (1mL) was added, then the reaction mixture was stirred for 2 h. Thereaction mixture was concentrated and the residue was taken up in EtOAc(2 mL). HCl in Et₂O (1N) (2 mL) was added and the precipitated salt wascollected by filtration.N-[2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)ethyl]benzenesulfonamidehydrochloride (0.0335 g) was obtained in 90% yield. ¹H NMR (300 MHz,CD₃OD) δ3.16, 3.19-3.23, 3.37-3.41, 3.44-3.47, 3.53-3.57, 4.34, 7.08,7.15, 7.32, 7.49, 7.52, 7.61, 7.77; MS (ESI+) for C₂₀H₂₃N₃O₂S m/z 370.1(M+H)⁺.

[0692] Preparation 46

[0693] Preparation of3-(3-(tert-butoxycarbonyl)-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)propanoicacid

[0694] Sodium hydride (0.302 g, 7.55 mmol, 2.16 equiv., 60% dispersion)was added to a solution of tert-butyl1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (1.00 g, 3.49mmol) in DMF (15 mL) at rt under N₂ and the mixture was stirred for 1.66h. β-Propiolactone (0.55 mL, 0.629g, 8.73 mmol, 2.5 equiv.) was added infour portions over 1 h, then the reaction mixture was stirred for 72 hat rt. The reaction mixture was partitioned between EtOAc (50 mL) and10% citric acid (25 mL), and the layers were separated. The organiclayer was washed with 10% citric acid. The combined aqueous layers wereextracted with EtOAc (25 mL). The combined organic layers were washedwith brine (25 mL), dried over MgSO₄, filtered, and concentrated. Thecrude product (2.27 g) was dissolved in CH₃OH (30 mL), then water (5 mL)and K₂CO₃ (2.10 g. 15.2 mmol) was added, and the reaction mixture wasstirred overnight. The reaction mixture was concentrated, and theresidue was partitioned between EtOAc (100 mL) and water (100 mL). Theorganic layer was extracted with 10% aq. Na₂CO₃ (2×50 mL) and 1N NaOH(2×50 mL). The combined aqueous layers were made acidic (pH=2) by theaddition of 2.9 M HCl and 10% aq. citric acid. The acidified aqueousmixture was extracted with EtOAc (3×100 mL). The organic extracts werewashed with water (50 mL) followed by brine (50 mL), dried over MgSO₄,filtered, and concentrated. The crude product (1.06 g) waschromatographed (SiO₂ 109 g, eluted with 4% MeOH in CH₂Cl₂ followed by10% MeOH in CH₂Cl₂) to give3-(3-(tert-butoxycarbonyl)-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)propanoicacid (0.796 g) in 63% yield. ¹H NMR (300 MHz, CDCl₃) δ1.51 (s, 9H),2.78, 2.99-3.08, 3.67-3.81, 4.42, 7.13, 7.20, 7.31, 7.49, 10.48; MS(ESI+) for C₂₀H₂₆N₂O₄ m/z 359.3 (M+H)⁺.

[0695] Preparation 47

[0696] Preparation of tert-butyl6-[3-(4-methoxyanilino)-3-oxopropyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0697]3-(3-(tert-butoxycarbonyl)-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)propanoicacid (0.105 g, 0.292 mmol), p-anisidine (0.0377 g, 0.306 mmol, 1.05equiv.) and dimethylaminopyridine (0.0357 g, 0.292 mmol, 1.00 equiv.)were dissolved in THF at rt under N₂. Diisopropylcarbodiimide (0.0503mL, 0.0405 g, 0.321 mmol, 1.00 equiv.) was added, then the reactionmixture was stirred for 29 h. The reaction mixture was taken up in EtOAcand washed with 10% aq. citric acid (2×), saturated aq. NaHCO₃ (2×) andbrine (1×). The organic layer was dried over MgSO₄, filtered, andconcentrated. The crude product (0.1686 g) was chromatographed (SiO₂ 25g, eluted with 9:1 toluene: acetone) to give tert-butyl6-[3-(4-methoxyanilino)-3-oxopropyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.113 g) in 84% yield. ¹H NMR (300 MHz, CDCl₃) δ1.47, 2.68-2.76,2.95-3.08, 3.56-3.70, 3.79, 4.53, 6.83, 7.12-7.54; MS (ESI+) forC₂₇H₃₃N₃O₄ m/z 464.0 (M+H)⁺.

Example 164

[0698] Preparation ofN-(4-methoxyphenyl)-3-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)propanarnidehydrochloride

[0699] tert-butyl6-[3-(4-methoxyanilino)-3-oxopropyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.110 g, 0.238 mmol) was disolved in CH₂Cl₂ (5 mL) and trifluoroaceticacid (2.0 mL, 2.96 g, 26.0 mmol, 109 equiv.) was added. The resultingsolution was stirred at rt for 2.5 h. The reaction mixture wasconcentrated to dryness, and the residue was partitioned between EtOAcand 1N NaOH. The layers were separated, and the aqueous layer wasextracted with EtOAc. The combined organic layers were washed withbrine, dried over MgSO₄, filtered, and concentrated. The crude product(0.0805 g) was combined with EtOAc (2 mL), and 1M HCl in Et₂O (2 mL) andthe salt was collected by filtration. The salt was dried under vacuumover P₂O₅.N-(4-methoxyphenyl)-3-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)propanamidehydrochloride (0.0796 g) was obtained in 84% yield. ¹H NMR (300 MHz,CD₃OD) δ2.76, 3.13-3.17, 3.28-3.39, 3.74, 4.55, 6.82, 7.08, 7.18, 7.26,7.44, 7.47; MS (ESI+) for C₂₂H₂₅N₃O₂ m/z 364.1 (M+H)⁺.

[0700] Preparation 48

[0701] Preparation of 2-[2-(1H-indol3-yl)ethyl]-1H-isoindole-1,3(2H)-dione

[0702] This compound was prepared by the reaction of tryptamine andN-carboethoxyphthalimide: TLC R_(f)=0.36 (CH₂Cl₂); MS (ESI+) m/z 291.0.

[0703] Preparation 49

[0704] Preparation of2-[2-[2-(1,1-dimethyl-2-propenyl)-1H-indol-3-yl]ethyl]-1H-isoindole-1,3(2H)-dione

[0705] To a solution of2-[2-(1H-indol-3-yl)ethyl]-1H-isoindole-1,3(2H)-dione (3.77 g, 13.0mmol) in dry THF (0.13 L) under argon was added NEt₃ (1.84 mL, 13.0mmol). This mixture was cooled to -78° C., and neat t-BuOCl (1.54 mL,13.0 mmol) was added. The reaction mixture was stirred for 30 min at−78° C. A solution of 9-(3-methyl-2-butenyl)-9-bora-bicyclo[3.3.1]nonane(40 mmol) in hexanes was added. The reaction mixture was stirred for 6 hat −78° C. It was quenched with 1 M aq HCl, and permitted to warm to rtovernight. The reaction mixture was extracted with CH₂Cl₂. The CH₂Cl₂extracts were dried, filtered, and concentrated to give an oil. The oilwas purified by silica chromatography to give the title compound: TLCR_(f)-0.36 (CH₂Cl₂); MS (ESI+) m/z 381.2, 359.2; ¹H NMR (300 MHz, CDCl₃)δ7.91 (1H), 7.88-7.69 (5H), 7.29 (1H), 7.10 (2H), 6.18 (1H), 5.25 (2H),3.95 (2H), 3.16 (2H), 1.61 (6H).

[0706] Preparation 50

[0707] Preparation of 2-(1,1-dimethyl-2-propenyl)-1H-indole-3-ethanamine

[0708] To a solution of2-[2-[2-(1,1-dimethyl-2-propenyl)-1H-indol-3-yl]ethyl]-1H-isoindole-1,3(2H)-dione(1.10 g, 3.07 mmol) in 3:1 MeOH/CH₂Cl₂ (20 mL) at rt under argon wasadded N₂H₄H₂O (0.52 mL). The reaction mixture was stirred overnight,concentrated in vacuo, diluted with CHCl₃, then extracted with H₂O. TheCHCl₃ layer was separated. The H₂O layer was extracted further withCHCl₃. The combined CHCl₃ extracts were washed, dried, filtered, andconcentrated to give the title compound: MS (ESI+) m/z 229.2.

[0709] Preparation 51

[0710] Preparation ofN-[2-[2-(1,1-dimethyl-2-propenyl)-1H-indol-3-yl]ethyl]-carbamic acidphenylmethyl ester

[0711] To a solution of 2-(1,1dimethyl-2-propenyl)-1H-indole-3-ethanamine (0.707 g, 3.07 mmol) in dryCH₂Cl₂ (30 mL) at 0° C. under argon was added NEt₃ (0.98 mL, 6.93 mmol)and BnOC(O)Cl (1.10 mL, 7.32 mmol). The reaction was permitted to warmto rt while stirring overnight. It was diluted with CH₂Cl₂, andextracted with cold H₂O. The CH₂Cl₂ layer was separated. The H₂O layerwas re-extracted with CH₂Cl₂. The combined CH₂Cl₂ extracts were washedwith satd aq NaHCO₃ and brine, dried, filtered and concentrated to givean oil. This oil was purified by silica chromatography to provide thetitle compound: TLC R_(f)=0.34 (CH₂Cl₂); MS (EI) m/z 362.3, 254, 211,198, 182. 168, 167, 108, 91, 77, 65, 51; ¹H NMR (300 MHz, CDCl₃) δ7.89(1H), 7.56 (1H), 7.33-7.26 (6H), 7.10 (2H), 6.12 (1H), 5.18-5.12 (2H),5.12 (2H), 4.87 (1H), 3.47 (2H), 3.07 (2H), 1.53 (6H).

[0712] Preparation 52

[0713] Preparation of(±)-N-[2-[2-(2,3-dihydroxy-1,1-dimethylpropyl)-1H-indol-3-yl]ethyl]-carbamicacid phenylmethyl ester

[0714] To a solution ofN-[2-[2-(1,1-dimethyl-2-propenyl)-1H-indol-3-yl]ethyl]-carbamic acidphenylmethyl ester (0.511 g, 1.41 mmol) and 4-methylmorpholine-N-oxide(0.187 g, 1.59 mmol) in 1:1 acetone/H₂O (14.2 mL) was added OSO₄ as a 39mM solution in tBuOH (2.5 mL). The reaction mixture was stirred for 18 hat rt. The reaction mixture was quenched by the addition of 7.1 mL of anaqueous slurry of Na₂S₂O₄ (0.088 g) and Florisl® (0.881 g). The mixturewas filtered. The filtrate was acidified to pH 4 with dilute aq H₂SO₄,and concentrated. The pH of the filtrate was adjusted to pH 2 withH₂SO₄. The mixture was extracted with EtOAc. The combined EtOAc extractswere washed with brine, dried, filtered, and concentrated to give anoil. The oil was purified by silica chromatography to give the titlecompound: TLC R_(f)=0.21 (4:1 EtOAc/hexanes); MS (ESI+) m/z 419.2,397.2; ¹H NMR (300 MHz, CDCl₃) δ8.80 (1H), 7.52 (1H), 7.33-7.26 (6H),7.16-7.06 (2H), 5.04 (1H), 5.04 (2H), 4.11 (1H), 3.85 (1H), 3.69 (1H),3.46 (1H), 3.31 (2H), 3.10 (2H), 2.04 (1H), 1.47 (6H).

[0715] Preparation 53

[0716] Preparation ofN-[2-[2-(1,1-dimethyl-2-oxoethyl)-1H-indol-3-yl]ethyl]-carbamic acidphenylmethyl ester

[0717] To a solution of(±)-N-[2-[2-(2,3-dihydroxy-1,1-dimethylpropyl)-1H-indol-3-yl]ethyl]-carbamicacid phenylmethyl ester (0.323 g, 0.81 mol) in 1:1 acetone/CH₂Cl₂ (19.5mL) was added NaIO₄ (0.350 g, 1.64 mmol) in H₂O (2.2 mL). The reactionmixture was stirred for 3 h at rt. Solid Na₂SO₄ was added. The mixturewas filtered. The filtrate was extracted with CH₂Cl₂. The CH₂Cl₂extracts were dried, filtered, and concentrated to an oil. This oil waspurified by silica chromatography to give the title compound: TLCR_(f)=0.31 (1:1 heptane/EtOAc); MS (ESI+) m/z 365.2; ¹H NMR (300 MHz,CDCl₃) δ9.56 (1H), 8.11 (1H), 7.64 (1H), 7.37 (5H), 7.21 (1H), 7.13(1H), 5.14 (2H), 4.92 (1H), 3.45 (2H), 2.95 (2H), 1.60 (6H).

Example 165

[0718] Preparation of5,5-dimethyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole hydrogen chloridesalt

[0719] A suspension ofN-[2-[2-(1,1-dimethyl-2-oxoethyl)-1H-indol-3-yl]ethyl]-carbamic acidphenylmethyl ester (0.200 g, 0.55 mol) and 10% Pd/C (0.080 g) in MeOH(40 mL) was hydrogenated at atmospheric pressure for 2 h. The mixturewas filtered. The filtrate was concentrated. The residue was taken up inMeOH (2 mL), and a solution of HCl in Et₂O was added. The precipitatewas collected and triturated with Et₂O. The solid was dried to give thetitle compound: MS (FAB) m/z 216.2, 215.2, 214.2, 213.1, 186.1, 184.1,177.0, 172.1; ¹H NMR (300 MHz, CD₃SOCD₃) δ10.88 (1H), 9.54 (1H), 7.42(1H), 7.32 (1H), 7.04 (1H), 6.97 (1H), 3.61 (2H), 3.39 (4H), 3.10 (2H),1.44 (6H); Anal. C 62.92, H 7.34, N 10.11.

[0720] Preparation 54

[0721] Preparation of 4-chloro-3-(1H)-indoleglyoxylic acid ethyl ester

[0722] To a solution of 4-chloroindole (5.00 g, 33.0 mmol) in dry THF(0.2 L), at 0° C. under argon was added (COCl)₂ (3.6 mL, 40.4 mmol). Thereaction mixture was stirred overnight while warming to rt, cooled to 0°C., and EtOH (4 mL, 69 mmol) was added. The reaction mixture was stirredat rt overnight, then partitioned between cold 0.2 M aq HCl and EtOAc.The aqueous layer was separated and re-extracted with EtOAc. The EtOAcextracts were washed with saturated aqueous NaHCO₃ and brine. Theextracts were dried, filtered, and concentrated to give a solid. Thesolid was purified by silica chromatography to give the title compound:TLC R_(f)=0.40 (19:1 CH₂Cl₂/Me₂CO); MS (ESI+) m/z 274.0; ¹H NMR (300MHz, CDCl₃) δ9.22 (1H ), 8.26 (1H), 7.36 (1H ), 7.31 (1H ), 7.22 (1H ),4.71 (2H), 1.41 (3H).

[0723] Preparation 55

[0724] Preparation of 2-(4-chloro-1H-indol-3-yl)-ethanol

[0725] To a solution of 4-chloro-3-(1H)-indoleglyoxylic acid ethyl ester(7.04 g, 30.0 mmol) in dry THF (0.4 L), at 0° C. under argon was addedportionwise LiAlH₄ (5.4 g, 135.2 mmol). The suspension was stirred at 0°C. for 20 min and at reflux for 3.5 h, cooled to 0° C., and water (17.6mL) was added. It was stirred for 10 min, and then diluted with EtOAc.The reaction mixture was filtered. The solid was washed with EtOAc. Thecombined EtOAc portions were washed with water and brine, dried,filtered, and concentrated to give the title compound: TLC R_(f)=0.38(9:1 CH₂Cl₂/Me₂CO); MS (ESI−) m/z 194.0; ¹³C NMR (75 MHz, CDCl₃)δ138.02, 126.42, 124.21, 124.12, 122.70, 120.61, 112.63, 110.06, 63.59,29.78.

[0726] Preparation 56

[0727] Preparation of 3 (2-azidoethyl)-4-chloro-1H-indole

[0728] To a mixture of 2-(4-chloro-1H-indol-3-yl)-ethanol (5.35 g, 27.3mmol), PPh₃ (14.35 g, 54.7 mmol), and Zn(N₃)₂.pyr₂ (12.1 g, 41.0 mmol)in PhCH₃ (0.14 L) was added iPrO₂CNNCO₂iPr (10.78 mL, 54.7 mmol). Thereaction mixture was stirred for 3.5 h at rt, then concentrated. Theresidue was purified by silica chromatography to give the titlecompound: TLC R_(f)=0.64 (CH₂Cl₂); MS (ESI−) m/z 219.0; ¹³C NMR (75 MHz,CDCl₃) δ137.80, 126.16, 124.07, 123.90, 122.78, 120.64, 112.73, 110.07,52.74, 26.21.

[0729] Preparation 57

[0730] Preparation of2-[3-(2-azidoethyl)-4-chloro-1H-indol-2-yl]-propanedioic acid dimethylester

[0731] To a solution of 3-(2-azidoethyl)-4-chloro-1H-indole (4.25 g,19.3 mmol) and NEt₃ (3.00 mL, 21.3 mmol) in THF (0.11 L) at −78° C.under argon was added dropwise tBuOCl (2.51 mL, 21.2 mmol). The solutionwas stirred for 30 min at −78° C. A solution of 1 M ZnCl₂ in Et₂O (4.1mL) was added. The reaction mixture was stirred for 20 min at −78° C. Asolution of lithiodimethyl malonate (23.1 mmol) in THF/hexanes (50 mL)was added at −78 ° C. The reaction mixture was stirred for 60 min. at-78° C., stirred at rt overnight, then diluted with cold H₂O. Themixture was extracted with Et₂O. The combined Et₂O extracts were washedwith H₂O , dried, filtered, and concentrated to give the title compound:TLC R_(f)=0.44 (CH₂Cl₂); MS (ESI−) 349.0; ¹H NMR (300 MHz, CDCl₃) δ9.14(1H), 7.25 (1H), 7.07 (2H), 5.10 (1H), 3.81 (6H), 3.57 (2H), 3.23 (2H).

[0732] Preparation 58

[0733] Preparation of2-[3-(2-azidoethyl)4-4-chloro-1H-indol-2-yl]-2-methylpropanedioic aciddimethyl ester

[0734] To a solution of2-[3-(2-azidoethyl)-4-chloro-1H-indol-2-yl]-propanedioic acid dimethylester (19.3 mmol) in dry MeOH (0.1 L) at 0° C. under argon was added a25% NaOMe in MeOH (4.37 mL, 19.11 mmol). The reaction mixture wasstirred for 30 min, and Mel (1.82 mL, 29.2 mmol) was added. The mixturewas stirred briefly at rt, and then was refluxed overnight. The reactionmixture was concentrated. The residue was taken up with cold H₂O. Thismixture was extracted with Et₂O. The combined Et₂O extracts were washedwith H₂O, dried, filtered, and concentrated to an oil. This oil waspurified by silica chromatography to give the title compound: TLCR_(f)=0.50 (CH₂Cl₂), MS (ESI+) 387.0; ¹H NMR (300 MHz CDCl₃) δ9.95 (1H),7.27 (1H), 7.07 (2H), 3.83 (6H), 3.48 (2H), 3.15 (2H), 1.94 (3H).

[0735] Preparation 59

[0736] Preparation of(±)-10-chloro-5-methyl-2,3,5,6-tetrahydroazepino[4,5-b]indol-4(1H)-one

[0737] To a solution of2-[3-(2-azidoethyl)-4-chloro-1H-indol-2-yl]-2-methylpropanedioic aciddimethyl ester (2.07 g, 5.67 mmol) in dry THF (50 mL) under argon at rtwas added 1 M PMe₃ in THF (9.7 mL). The reaction mixture was stirred for1.5 h at rt. Water (9.7 mL) was added. After 1.5 h at rt, the reactionmixture was concentrated. The residue was partitioned between CH₂Cl₂ andsaturated aqueous NaHCO₃. The CH₂Cl₂ extracts were combined, dried,filtered, and concentrated to give the amine as an oil. This oil wasdissolved in MeOH. This solution was refluxed under N₂ for 42 h. Thereaction mixture was cooled, and 1 M aq LiOH (28.5 mL) was added. Thereaction mixture was refluxed for 47 h. It was concentrated, and theresidue was taken up in EtOAc. The EtOAc solution was extracted withH₂O, dried, filtered, and concentrated to give the title compound: TLCR_(f)=0.25 (4:1 CH₂Cl₂/acetone); MS (ESI−) 247.0; ¹H NMR (300 MHz,CDCl₃) δ8.16 (1H), 7.18 (1H), 6.99 (2H), 6.12 (1H), 4.29 (1H), 3.83(1H), 3.55 (1H), 3.36 (2H), 1.64 (3H).

[0738] Preparation 60

[0739] Preparation of(R)-10-chloro-5-methyl-2,3,5,6-tetrahydroazepino[4,5-b]indol-4(1H)-one

[0740] The racemate (0.70 g) was resolved by chiral supportchromatography. Portions of the racemate (0.35 g dissolved in 20 mL of3:1 iPrOH/THF) were injected onto a preparative Chiralcel OD™ columnequilibrated at 30° C. with 800:200:1 heptane/iPrOHI/Et₃N. From theinjections were recovered the faster eluting S-enantiomer and theR-enantiomer. Analytical HPLC analysis (t_(R)=11.9 min on a Chiralcel™OD-H at a 0.4 mL min⁻¹ flow rate of 1000:1 EtOH/Et₂NH) gave an ee of91%: UV λ_(max) nm (ε, L.mol⁻¹.cm⁻¹) 284 (6840); CD λ_(max) nm (θ,deg.cm² dmol⁻¹) 300 (6700), 289 (7000), 279 (6500).

[0741] Preparation 61

[0742] Preparation of(S)-10-Chloro-5-methyl-2,3,5,6-tetrahydroazepino[4,5-b]indol-4(1H)-one

[0743] Analytical HPLC analysis (t_(R)=11.2 min on a Chiralcel™ OD-H ata 0.4 ML min⁻¹ flow rate of 1000:1 EtOH/Et₂NH) gave an ee of >99%: UVλ_(max) nm (ε, L.mol⁻¹.cm⁻¹) 284 (7560); CD λ_(max) nm (θ,deg.cm².dmol⁻¹) 300 (- 8200), 289 (−8800), 279 (−8500).

Example 166

[0744] Preparation of(R)-10-chloro-5-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(E)-butenedioic acid salt

[0745] A solution of 1 M iBu₂AlH in CH₂Cl₂ (15.3 mL) was mixed with dryTHF (10 mL) at −78° C. After stirring this mixture for 5 min, a solutionof(R)-10-chloro-5-methyl-2,3,5,6-tetrahydroazepino[4,5-b]indol-4(1H)-one(0.251 g, 1.01 mmol) in THF (15 mL) was added. The reaction mixture wasallowed to warm to rt, stirred at rt for 7 days, cooled to 0° C., thenquenched by the addition of MeOH (4.5 mL). The reaction mixture wasdiluted with CH₂Cl₂ and 1 M aq KO₂CCH(OH)CH(OH)CO₂Na. This mixture wasstirred for 1 h. The CH₂Cl₂ layer was separated. The aqueous mixture wasextracted further with CH₂Cl₂. The combined CH₂Cl₂ extracts were washedwith brine, dried, filtered, and concentrated to give an oil. This oilwas purified by silica chromatography to give the amine. A solution ofthis amine (0.087 g, 0.37 mmol) in anhydrous MeOH (4 mL) was mixed at rtwith a solution of fumaric acid (0.021 g, 0.185 mmol) in MeOH (2 mL).The mixture was stirred at rt for 18 h, then concentrated. The solidresidue was taken up in hot MeOH (14 mL), that upon standing at rt for 3days yielded 0.048 g (0.164 mmol, 38%) of the title compound as acrystalline tan-colored solid: MS (EI) m/z 234, 205, 204, 199, 194, 192,190, 155, 154, 77; ¹H NMR(300 MHz, CD₃SOCD₃) δ11.14 (1H), 7.23 (1H),6.94 (2H), 6.43 (1H), 3.52-2.83 (8H), 1.31 (3H); Anal. C 60.62, H 6.02,N 9.27.

Example 167

[0746] Preparation of(S)-10-chloro-5-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(E)-butenedioic acid salt

[0747] The crystalline salt was prepared as described for(R)-10-chloro-5-methyl-2,3,5,6-tetrahydroazepino[4,5-b]indol-4(1H)-onein Example 166. These crystals occupy the monoclinic space group P21with Z=4. The absolute configuration was determined as S by singlecrystal x-ray analysis. Intensity data from a 0.50∝0.22∝0.08 mm paleyellow plate crystal were measured at 153° K, on a Brucker SMART 600™area detector using graphite monochromatized copper radiation[λ(CuKα)=1.5418 Å]. All reflections to a resolution of 0.90, and theirFreidel equivalents, were measured (3533 reflections total) andface-indexed absorption corrections were applied. The structure wassolved, and the data were refined, using the SHELXTL™ computer program.The final agreement index R was 0.0508 for all reflections. The Flackparameter was −0.030 (0.016). A Flack parameter within 3 standarddeviations of zero indicates the correct assignment of absoluteconfiguration (the opposite enantiomer should have a Flack value ofone). Refinement of the coordinates for the other enantiomer gave an Rvalue of 0.065 and a Flack value of 0.973(0.025), verifying theassignment of absolute configurations: mp 276-278° C.; MS (ESI) m/z237.0, 235.0; Anal. C 61.05, H 5.95, N 9.41.

[0748] Preparation 62

[0749] Preparation of 6-fluoro-3-indoleglyoxylic acid ethyl ester

[0750] To a solution of 6-fluoroindole (1.18 g, 8.56 mmol) in dry THF(65 mL) at 0° C. under argon was added (COCl)₂ (0.93 mL, 10.7 mmol). Thereaction mixture was stirred at 0° C. for 2 h and at rt for 15 h. Thereaction mixture was cooled to 0° C. and EtOH (0.90 mL, 15.5 mmol) wasadded. The reaction mixture was stirred at rt for 24 h, then poured intocold satd NaHCO₃. The mixture was extracted with EtOAc. The combinedEtOAc extracts were washed with satd aq NaHCO₃ and brine, dried, andevaporated to give the title compound: TLC R_(f)=0.48 (19:1CH₂Cl₂/Me₂CO); MS (ESI−) m/z 234.0; ¹H NMR (CDCl₃, 300 MHz) δ10.95 (1H),8.38 (1H), 8.31 (1H), 7.07 (1H), 4.37 (2H), 1.39 (3H).

[0751] Preparation 63

[0752] Preparation of 2-(6-fluoro-1H-indol-3-yl)-ethanol

[0753] To a solution of 6-fluoro-3-indoleglyoxylic acid ethyl ester(2.01 g, 8.55 mmol) in dry THF (0.11 L) at 0° C. under argon was addedLiAlH₄ (1.68 g, 44.2 mmol). The reaction mixture was refluxed for 3 h,cooled to 0° C., and treated with H₂O (1.7 mL), 15% aq KOH (1.7 mL), andH₂O (5 mL). The mixture was filtered. The filtrate was diluted withEtOAc, and washed with H₂O and brine. The EtOAc solution was dried,filtered, and concentrated to give the title compound: TLC R_(f)=0.33(9:1 CH₂Cl₂/Me₂CO); MS (ESI−) m/z 178.0; ¹H NMR (CDCl₃, 300 MHz) δ8.38(1H), 7.49 (1H), 7.01-6.63 (3H), 3.90 (2H), 2.99 (2H), 2.23 (1H).

[0754] Preparation 64

[0755] Preparation of 3-(2-azidoethyl)-6fluoro-1H-indole

[0756] To a mixture of 2-(6-fluoro-1H-indol-3-yl)-ethanol (3.16 g, 17.6mmol), PPh₃ (9.26 g, 35.3 mmol), and Zn(N₃)₂.(pyridine)₂ (7.80 g, 26.5mmol) in dry PhCH₃ (0.08 L) at rt was added iPrO₂CNNCO₂iPr (7.0 mL, 35.3mmol). The reaction mixture was stirred at rt for 4 h, concentrated to aresidue, then purified by silica chromatography to give the titlecompound: TLC R_(f)=0.63 (CH₂Cl₂); MS (ESI−) m/z 203.0; ¹H NMR (CDCl₃,300 MHz) δ8.03 (1H), 7.50 (1H), 7.06 (2H), 6.91 (1H), 3.56 (2H), 3.04(2H).

[0757] Preparation 65

[0758] Preparation of2-[3-(2-azidoethyl)-6-fluoro-1H-indol-2-yl]-propanedioic acid dimethylester

[0759] To a solution of 3-(2-azidoethyl)-6-fluoro-1H-indole (4.77 g,23.3 mmol) and NEt₃ (3.63 mL, 25.8 mmol) in dry THF (0.13 L) at −78° C.under argon was added tBuOCl (3.04 mL, 26.9 mmol). The reaction mixturewas stirred for 30 min at −78° C. A solution of 1 M ZnCl₂ in Et₂O (5.0mL) was added. After 15 min a solution of dimethyl lithiomalonate (28.1mmol in THF/hexanes) was added. The mixture was stirred at −78° C. for 1h and at rt overnight, diluted with cold water, then extracted withEt₂O. The Et₂O extracts were dried, filtered, and concentrated to givethe title compound: TLC R_(f)=0.46 (CH₂Cl₂); MS (ESI−) m/z 333.1; ¹H NMR(CDCl₃, 300 MHz) δ8.97 (1H), 7.45 (1H), 7.05 (1H), 6.89 (1H), 5.02 (1H),3.80 (6H), 3.50 (2H), 2.97 (2H).

[0760] Preparation 66

[0761] Preparation of8-fluoro-2,3,5,6-tetrahydroazepino[4,5-b]indol-4(1H)-one

[0762] A suspension of2-[3-(2-azidoethyl)-6-fluoro-1H-indol-2-yl]-propanedioic acid dimethylester (2.05 g, 6.13 mmol) and 10% Pd/C (0.69 g) in MeOH (0.15 L) washydrogenated at atmospheric pressure for 2 h. The mixture was filtered.The MeOH solution was refluxed overnight. The reaction mixture wascooled, and most of the MeOH solvent was evaporated. The mixture waspurified by silica chromatography (steps of 4:1 to 7:3 CH₂Cl₂/Me₂CO) togive the carboxylactam. To a solution of the carboxylactam (1.37 g, 4.11mmol) in MeOH (0.2 L) at rt under N₂ was added a solution of 1 M aqLiOH.H₂O (21 mL). The mixture was refluxed overnight, and thenconcentrated. The residue was partitioned between EtOAc and H₂O. TheEtOAc extracts were filtered and concentrated to give a solid, that waspurified by silica chromatography to give the title compound: TLCR_(f)=0.14 (9:1 CH₂Cl₂/satd NH₃ in MeOH); MS (ESI−) m/z 217.0 [M−H]^(−;)¹H NMR (CDCl₃, 300 MHz) δ9.53 (1H), 7.24 (1H), 6.94 (1H), 6.74 (1H),6.35 (1H), 3.79 (2H), 3.60 (2H), 2.85 (2H).

Example 168

[0763] Preparation of 8-Fluoro 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole0.5 (E)-butenedioic acid salt

[0764] To a flask containing THF (10 mL) at −78° C. under argon wasadded a 1 M solution of iBU₂AlH in CH₂Cl₂ (16.3 mL). After 5 min, asolution of 8-fluoro-2,3,5,6-tetrahydroazepino[4,5-b]indol-4(1H)-one(0.175 g, 0.80 mmol) in THF (16 mL) was added. The reaction mixture wasallowed to warm to rt, stirred for 48 h, cooled to 0° C., then quenchedwith MeOH (4.5 mL). It was partitioned between CH₂Cl₂ and aqueous 1 MKO₂CC(OH)C(OH)CO₂Na. The CH₂Cl₂ extracts were washed with brine, dried,filtered, and concentrated to give a solid. The solid was purified bysilica chromatography (92.5:7.5 CH₂Cl₂/satd NH₃ in MeOH) to give thefree armine. A solution of this amine (0.094 g, 0.46 mmol) in dry MeOH(4.0 mL) at rt under argon was mixed with a solution of fumaric acid(0.027 g, 0.23 mmol) in dry MeOH (2.2 mL). The turbid solution wasstirred overnight at rt. The MeOH was evaporated. The residue wasdissolved in hot MeOH, and the salt was permitted to crystallize. Thecrystalline salt was collected: mp 266° C.; MS (ESI+) m/z 205.1; ¹H NMR(CD₃SOCD₃, 300 MHz) δ10.94 (1H), 7.34 (1H), 7.00 (1H), 6.77 (1H), 6.40(1H), 3.11 (4H), 2.91 (4H); Anal. C 63.90, H 5.83, N 10.63.

[0765] Preparation 67

[0766] Preparation of2-[3-(2-azidoethyl)-6-fluoro-1H-indol-2-yl]-2-methylpropanedioic aciddimethyl ester

[0767] To a solution of2-[3-(2-azidoethyl)-6-fluoro-1H-indol-2-yl]-propanedioic acid dimethylester (37 mmol) in dry MeOH (0.25 L) at 0° C. under argon was added asolution of 25% NaOMe in MeOH (8.56 mL, 37.4 mmol). The mixture wasstirred for 30 min at 0° C. Mel (3.56 mL, 56.6 mmol) was added. Themixture was refluxed for 42 h, cooled, and concentrated. The residue waspartitioned between H₂O and Et₂O. The Et₂O extracts were washed with H₂O, dried, and concentrated to an oil. This oil was purified by silicachromatography to give the title compound: TLC R_(f)=0.50 (CH₂Cl₂); MS(ESI+) m/z 371.1; ¹H NMR (CDCl₃, 300 MHz) δ9.63 (1H), 7.44 (1H), 7.05(1H), 6.97 (1H), 3.82 (6H), 3.44 (2H), 2.94 (2H), 1.93 (3H).

[0768] Preparation 68

[0769] Preparation of(±)-8-fluoro-5-methyl-2,3,5,6-tetrahydroazepino[4,5-b]indol-4(1H)-one

[0770] A mixture of2-[3-(2-azidoethyl)-6fluoro-1H-indol-2-yl]-2-methylpropanedioic aciddimethyl ester (3.10 g, 8.90 mmol) and 10% Pd/C (0.87 g) in MeOH (0.2 L)was hydrogenated at atmospheric pressure for 2.5 h. The reaction mixturewas filtered. The filtrate was refluxed for 18 h. The reaction mixturewas concentrated to give the carboxylactam. A solution of thecarboxylactam (2.08 g, 5.96 mmol) in MeOH (0.27 L), and a 1 M LiOH.H₂Oin MeOH solution (0.030 L), were combined at rt. The mixture wasrefluxed for 42 h, cooled, and concentrated. The MeOH solution wasdiluted with H₂O , and the aqueous solution was extracted with EtOAc.The EtOAc extracts were concentrated to give the title compound: MS(ESI−) m/z 231.0; ¹H NMR (300 MHz, CDCl₃) δ8.04 (1H), 7.31 (1H), 7.10(1H), 6.86 (1H), 6.16 (1H), 4.24 (1H), 3.86 (1H), 3.58 (1H), 2.96 (2H),1.64 (3H).

[0771] Preparation 69

[0772] Preparation of(R)-8-fluoro-5-methyl-2,3,5,6-tetrahydroazepino[4,5-b]indol-4(1H)-one

[0773] The racemate was resolved by chiral support chromatography.Portions of the racemate (0.2 g dissolved in 10 mL of 3:1 iPrOH/THF)were injected onto a preparative Chiralcel OD™ column equilibrated at30° C. with 800:200:1 heptane/iPrOH/Et₃N. Assignment of absoluteconfigurations to the separated enantiomers was made by comparison ofthe CD spectra to those of the 10-chloro strictures. Analytical HPLCanalysis (t_(R)=17.2 min on a Chiralcel™ OD-H at a 0.5 mL min⁻¹ flowrate of 800:200:1 hepane/iPrOH/Et₂NH) gave an ee of 97%: UV λ_(max) nm(ε, L.mol⁻¹.cm⁻¹) 284 (4740); CD λ_(max) nm (θ, deg.cm².dmol⁻¹) 298(3700), 273 (4400).

[0774] Preparation 70

[0775] Preparation of(S)-8-fluoro-5-methyl-2,3,5,6-tetrahydroazepino[4,5-b]indol-4(1H)-one

[0776] Analytical HPLC analysis (t_(R)=15.2 min on a Chiralcel™ OD-H ata 0.5 mL min⁻¹ flow rate of 800:200:1 hepane/iPrOH/Et₂NH) gave an eeof >99%: UV λ_(max) nm (ε, L.mol⁻¹.cm⁻¹) 292 (4540); CD λ_(max) nm (θ,deg.cm².dmol⁻¹) 297 (−3000), 273 (−4000).

Example 169

[0777] Preparation of(R)-8-fluoro-5-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole 0.5(E)-butenedioic acid salt

[0778] To an ovendried flask containing dry THF (10 mL) under argon at−78° C. was added a 1 M solution of (iBu)₂AlH in CH₂Cl₂ (16.3 mL). Thismixture was stirred at −78° C. for 5 min. To this was(R)-8-fluoro-5-methyl-2,3,5,6tetrahydroazepino[4,5-b]indol-4(1H)-one(0.236 g, 1.02 mmol) in dry THF (16 mL). The reaction mixture wasstirred at rt for 72 h, cooled to 0° C., then quenched by the additionof MeOH (4.5 mL). The mixture was partitioned between CH₂Cl₂ and 1 M aqNaO₂CCH(OH)CH(OH)CO₂K. The CH₂Cl₂ extracts were washed with brine, anddried, filtered and concentrated to give an oil. The oil was purified bysilica chromatography to give the amine. To a solution of this amine(0.105 g, 0.48 mmol) in dry MeOH (4 mL) was added fumaric acid (0.028 g,0.24 mmol) in MeOH (2.2 mL). The mixture was stirred overnight,concentrated, and the residue was dissolved in hot MeOH from whichcrystalline product was recovered: mp 256258° C.; MS (ESI+) m/z 219.1;¹H NMR (CD₃SOCD₃, 300 MHz) δ10.83 (1H), 9.3-8.5 (2H), 7.35 (1H), 7.01(1H), 6.78 (1H), 6.43 (1H), 3.22-2.70 (8H), 1.30 (3H); Anal. C 64.94, H6.27, N 10.07.

Example 170

[0779] Preparation of(S)-8-fluoro-5-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole 0.5(E)-butenedioic acid salt

[0780] This salt was prepared by the method taught for the R-enantiomerin Example 169: mp 254-256° C.; MS (ESI+) m/z 219.1; Anal. C 64.83, H6.23, N 10.05.

Example 171

[0781] Preparation of2-(7-bromo-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(4-methoxyphenyl)acetamidehydrochloride

[0782] Prepared according to the procedure used to prepareN-(2,3-dimethylphenyl)-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-7yl)acetamidehydrochloride. ¹H NMR (CD₃OD) δ7.51, 7.47, 7.34, 6.98, 7.90, 5.53, 3.78,3.51, 3.24. MS (ESI+) for C₂₁H₂₂BrN₃O₂ m/z 428.1 (M+H)⁺.

Example 172

[0783] Preparation ofN-pyridin-2-yl-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamide

[0784] Prepared according to the procedure used to prepareN-(2,3-dimethylphenyl)-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamidehydrochloride. ¹H NMR (CD₃OD) δ8.30, 8.05, 7.76, 7.49, 7.32, 7.16-7.06,5.10, 3.27-3.23, 3.11-3.04. MS (ESI+) for C₁₉H₂₀N₄O m/z 321.2 (M+H)⁺.

Example 173

[0785] Preparation ofN-pyridin-3-yl-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamide

[0786] Prepared according to the procedure used to prepareN-(2,3-dimethylphenyl)-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamidehydrochloride in 30% yield. ¹H NMR (CD₃OD) δ8.74, 8.28, 8.11, 7.46,7.40, 7.29, 7.13, 7.05, 5.04, 3.16-3.10, 3.05-2.99; MS (ESI+) forC₁₉H₂₀N₄O m/z 321.2 (M+H)⁺.

[0787] Preparation 71

[0788] Preparation of tert-Butyl8,9-dichloro-6-(2-ethoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0789] Sodium hydride (60% dispersion in mineral oil, 0.34 g, 8.5 mmol)was added to a solution of tert-butyl 8,9-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (2.00 g,5.63 mmol) in DMF (30 mL). After 20 min, ethyl bromoacetate (1.25 mL,11.3 mmol) was added. The reaction was quenched with saturated aqueousNH₄Cl after 4 h and extracted with EtOAc (3×50 mL). The combined organicextracts were washed with brine, dried over Na₂SO₄, decanted, andconcentrated. The crude product was purified by column chromatographywith heptane/EtOAc (3:1) to give 2.10 g (84%) of a pale yellow solid: mp137.5-139.5° C.; IR (diffuse reflectance) 2985, 1742, 1687, 1473, 1411,1377, 1367, 1341, 1318, 1249, 1218, 1193, 1167, 1118, 922 cm⁻¹; MS (CI)m/z 441 (M+H⁺), 404, 402, 387, 385, 343, 341, 339, 307, 52, 51; Anal.Calcd for C₂₁H₂₆Cl₂N₂O₄: C, 57.15; H, 5.94; N, 6.35; found: C, 57.13; H,6.05; N, 6.24.

[0790] Preparation 72

[0791] Preparation of[3-(tert-Butoxycarbonyl)-8,9-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl]aceticacid

[0792] A solution of KOH (0.17 g, 3.0 mmol) in H₂O (10 mL) was added toa solution of tert-butyl8,9-dichloro-6-(2-ethoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(1.00 g, 2.27 mmol) in THF (15 mL). The mixture was heated at 60° C. for2 h. The reaction was then cooled to rt, acidified with 10% aqueous HCl,and extracted with EtOAc (3×30 mL). The combined organic extracts werewashed with brine, dried over Na₂SO₄, decanted, and concentrated to givecrude acid (1.03 g, 110%): ¹H NMR (300 MHz, CDCl₃) δ7.50 (s, 1H), 7.26(s, 1H), 4.73 (s, 2H), 3.74 (m, 2H), 3.67 (m, 2H), 2.89 (m, 4H), 1.47(s, 9H); MS(ESI+) m/z 410.9.

[0793] Preparation 73

[0794] Preparation of tert-Butyl6-(2-anilino-2-oxoethyl)-8,9-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0795] DMAP (60 mg, 0.49 mmol), aniline (0.050 mL, 0.55 mmol) and DIC(0.084 mL, 0.54 mmol) were added to the solution of crude[3-(tert-butoxycarbonyl)-8,9-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl]aceticacid (0.20 g, 0.48 mmol) in dry THF (2.5 mL). After 18 h, the reactionwas diluted with EtOAc followed by washing with 10% aqueous citric acid,saturated aqueous NaHCO₃, and brine. The organic layer was then driedover-Na₂SO₄, decanted, and concentrated. The crude product was firstpurified by column chromatography (Biotage, 40S, SIM) with CH₂Cl₂/EtOAc(98:2) to give 0.12 g of impure product. Then, crystallization fromEtOAc/heptane gave 91 mg (39%) of a white solid: mp 172.5° C.; IR(diffuse reflectance) 3288, 1699, 1661, 1602, 1550, 1498, 1472, 1442,1421, 1367, 1309, 1298, 1268, 1252, 1162cm⁻¹; MS (CI) m/z 488 (M+H⁺),390, 388, 354, 153, 152, 136, 95, 93, 52, 51; Anal. Calcd forC₂₅H₂₇Cl₂N₃O₃: C, 61.48; H, 5.57; N, 8.60; found: C, 61.49; H, 5.67; N8.51.

Example 174

[0796] Preparation of2-(8,9-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-phenylacetamidehydrochloride

[0797] TFA (0.10 mL, 1.3 mmol) was added to a solution of tert-butyl6-(2-anilino-2-oxoethyl)-8,9-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(60 mg, 0.12 mmol) in CH₂Cl₂ (2 mL). The reaction was quenched with 10%aqueous NaOH (5 mL) after 2 h and extracted with CH₂Cl₂ (3×10 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄,decanted, and concentrated to give 46 mg of crude solid. Thehydrochloride salt was prepared to give 32 mg (62%) of a pale yellowsolid: mp 292-297.5° C. (dec); IR (diffuse reflectance) 2960, 2883,2817, 2805, 2769, 2715, 1682, 1601, 1550, 1498, 1466, 1447, 1313, 869,759 cm⁻¹; MS (EI) m/z 387 (M⁺), 347, 345, 188, 166, 92, 78, 76, 74, 66,51; HRMS (FAB) calcd for C₂₀H₁₉Cl₂N₃O+H 388.0983, found 388.0973; Anal.Calcd for C₂₀H₁₉Cl₂N₃O.HCl: C, 56.55; H, 4.75; N, 9.89; found: C, 56.78;H, 5.04; N, 9.50.

[0798] Preparation 74

[0799] Preparation of tert-Butyl8,9-dichloro-6-[2-(4-methoxyanilino)-2-oxoethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0800] DMAP (60 mg, 0.49 mmol), p-anisidine (66 mg, 0.54 mmol) and DIC(0.084 mL, 0.54 mmol) were added to the solution of crude[3-(tert-butoxycarbonyl)-8,9-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl]aceticacid (0.20 g, 0.48 mmol) in dry THF (2.5 mL). After 18 h, the reactionwas diluted with EtOAc and washed with 10% aqueous citric acid,saturated aqueous NaHCO₃, and brine. The organic layer was then driedover Na₂SO₄, decanted, and concentrated. The crude product was firstpurified by column chromatography (Biotage, 40S, SIM) with CH₂Cl₂/EtOAc(gradient, 99:1 to 95:5) to give 81 mg of impure product. Then,crystallization from EtOAc/heptane gave 73 mg (29%) of a white solid: mp151-151.5° C.; IR (diffuse reflectance) 3288, 1695, 1661, 1550, 1513,1473, 1422, 1367, 1318, 1269, 1250, 1172, 1161, 1118, 831 cm⁻¹; MS (CI)m/z 518 (M+H⁺), 222, 221, 220, 167, 166, 124, 59, 58, 52, 51; Anal.Calcd for C₂₆H₂₉Cl₂N₃O₄: C, 60.24; H, 5.64; N, 8.10; found: C, 60.23; H,5.73; N, 8.10.

Example 175

[0801] Preparation of2-(8,9-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(4-methoxyphenyl)acetamidehydrochloride

[0802] TFA (0.25 mL, 3.2 mmol) was added to a solution of tert-butyl8,9-dichloro-6-[2-(4-methoxyanilino)-2-oxoethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(50 mg, 0.096 mmol) in CH₂Cl₂ (3.0 mL). After 1.5 h, the reaction wasquenched with 10% aqueous NaOH and extracted with CH₂Cl₂ and EtOAc. Thecombined organic layers were washed with brine, dried over Na₂SO₄,decanted, and concentrated to 39 mg of a crude solid. The hydrochloridesalt was prepared to give 22 mg (50%) of off-white crystals: mp 294-299°C. (dec); IR (diffuse reflectance) 3248, 2964, 2959, 2907, 2883, 2855,2840, 2820, 2772, 1676, 1549, 1511, 1466, 1251, 823 cm⁻¹; MS (EI) m/z417 (M⁺), 389, 387, 375, 238, 224, 162, 136, 134, 127, 108; Anal. Calcdfor C₂₁H₂₁Cl₂N₃O₂.HCl: C, 55.46; H, 4.88; N, 9.24; found: C, 55.37; H,4.80; N, 9.15.

[0803] Preparation 75

[0804] Preparation of tert-Butyl8,9-dichloro-6-[2-(2,3-dimethylanilino)-2-oxoethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0805] DMAP (60 mg, 0.49 mmol), 2,3-dimethylaniline (0.065 mL, 0.53mmol) and DIC (0.084 mL, 0.54 mmol) were added to the solution of crude[3-(tert-butoxycarbonyl)-8,9-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl]aceticacid (0.20 g, 0.48 mmol) in dry THF (2.5 mL). After 18 h, the reactionwas diluted with EtOAc followed by washing with 10% aqueous citric acid,saturated aqueous NaHCO₃, and brine. The organic layer was then driedover Na₂SO₄, decanted, and concentrated. The crude product was firstpurified by column chromatography (Biotage, 40S, SIM) with CH₂Cl₂/EtOAc(98:2) to give 0.13 g of impure product. Then, crystallization fromEtOAc/heptane gave 96 mg (38%) of a white solid: mp 186-187.5° C.; IR(diffuse reflectance) 3290, 2977, 2939, 1692, 1681, 1662, 1538, 1471,1450, 1412, 1366, 1338, 1282, 1235, 1163 cm⁻¹; MS (EI) m/z 515 (M⁺),375, 373, 226, 225, 223, 120, 84, 76, 56, 51; Anal. Calcd forC₂₇H₃₁Cl₂N₃O₃: C, 62.79; H, 6.05; N, 8.14; found: C, 62.60; H, 6.04; N,8.07.

Example 176

[0806] Preparation of2-(8,9-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(2,3-dimethylphenyl)acetamidehydrochloride

[0807] TFA (0.25 mL, 3.2 mmol) was added to a solution of tert-butyl8,9-dichloro-6-[2-(2,3-dimethylanilino)-2-oxoethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(50 mg, 0.097 mmol) in CH₂Cl₂ (3.0 mL). After 1.5 h, the reaction wasquenched with 10% aqueous NaOH and extracted with CH₂Cl₂. The combinedorganic layers were washed with brine, dried over Na₂SO₄, decanted, andconcentrated to give 41 mg of a crude solid. The hydrochloride salt wasprepared to give 25 mg (56%) of pale yellow needles: mp 289-293° C.(dec); IR (diffuse reflectance) 3278, 2973, 2954, 2801, 2747, 2721,2689, 2633, 1656, 1536, 1466, 1448, 1427, 1293, 870 cm⁻¹; MS (EI) m/z415 (M⁺), 374, 372, 224, 119, 84, 77, 73, 63, 61, 51; Anal. Calcd forC₂₂H₂₃Cl₂N₃O.HCl: C, 58.35; H, 5.34; N, 9.28; found: C, 58.10; H, 5.36;N, 9.17.

[0808] Preparation 76

[0809] Preparation of tert-Butyl9,10-dichloro-6-(2-ethoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0810] To a solution of tert-butyl9,10-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.10 g, 0.28 mmol) in DMF (2 mL), sodium hydride (60% dispersion inmineral oil, 17 mg, 0.42 mmol) was added. After 15 min, ethylbromoacetate(0.060 mL, 0.56 mmol) was added. The reaction was quenchedwith saturated aqueous NH₄Cl after 2.5 h and extracted with EtOAc (3×15mL). The combined organic extracts were washed with brine, dried overNa₂SO₄, decanted, and concentrated. The crude product was purified bycolumn chromatography (Biotage, 40S) with heptane/EtOAc (3:1) to give 85mg (70%) of a white solid: mp 136.5-138.0° C.; ¹H NMR (300 MHz, CDCl₃)δ7.19 (d, J=8.7 Hz, 1H), 6.99 (d, J=8.7 Hz, 1H), 4.74 (s, 2H), 4.21 (dd,J=7.1, 7.1 Hz, 2H), 3.75 (m, 4H), 3.53 (m, 2H), 2.93 (m, 2H), 1.48 (s,9H), 1.26 (t, J=7.1 Hz, 3H); IR (diffuse reflectance) 2985, 2976, 1737,1685, 1466, 1450, 1414, 1367, 1344, 1249, 1213, 1169, 1156, 1115, 926cm⁻¹; MS (EI) m/z 440 (M⁺), 307, 305, 301, 299, 298, 272, 225, 189, 58,56; Anal. Calcd for C₂₁H₂₆Cl₂N₂O₄: C, 57.15; H, 5.94; N, 6.35, found: C,57.16; H, 5.98; N, 6.27.

[0811] Preparation 77

[0812] Preparation of[3-(tert-Butoxycarbonyl)-9,10-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl]aceticacid

[0813] To a solution of tert-butyl9,10-dichloro-6-(2-ethoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(1.5 g, 3.4 mmol) in THF (15 mL), a solution of KOH (25 mg, 4.4 mmol)dissolved in H₂O (10 mL) was added and heated to 60° C. The reaction wascooled to rt after 2 h. The reaction was made acidic with 10% aqueousHCl and extracted with EtOAc (3×30 mL). The combined organic extractswere washed with brine, dried over Na₂SO₄, decanted, and the crude acidwas concentrated: ¹H NMR (300 MHz, DMSO) δ13.11 (br s, 1H), 7.43 (d,J=8.8 Hz, 1H), 7.23 (d, J=8.7 Hz, 1H), 5.04 (s,2H), 3.62 (m, 4H), 2.93(m, 2H), 1.41 (s, 9H); HRMS (FAB) calcd for C₁₉H₂₂Cl₂N₂O₄+H 413.1035,found 413.1050.

[0814] Preparation 78

[0815] Preparation of tert-Butyl6-(2-anilino-2-oxoethyl)-9,10-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0816] DMAP (60 mg, 0.49 mmol), aniline (0.050 mL, 0.55 mnmol) and DIC(0.084 mL, 0.54 mmol) were added to the solution of crude[3-(tert-butoxycarbonyl)-9,10-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl]acetic acid(0.20 g, 0.48 mmol) in dry THF (2.5 mL). After 24 h, the reaction wasdiluted with EtOAc followed by washing with 10% aqueous citric acid (20mL), saturated aqueous NaHCO₃ (20 mL), and brine (20 mL). The organiclayer was then dried over Na₂SO₄, decanted, and concentrated. The crudeproduct was first purified by column chromatography (Biotage, 40S, SIM)with CH₂Cl₂/EtOAc and yielded 0.16 g of impure product. Then,crystallization from EtOAc/heptane gave 90 mg (37%) of a white solid; mp208.5-210.0° C.; ¹H NMR (300 MHz, DMSO) δ10.45 (s, 1H), 7.58 (d, J=8.3Hz, 2H), 7.45 (d, J=9.0 Hz, 1H), 7.30 (m, 3H), 7.07 (m, 1H), 5.08 (br s,2H), 3.63 (m, 4H), 3.40 (m, 2H), 2.99 (m, 2H), 1.40 (app d, 9H); IR(diffuse reflectance) 3275, 1693, 1671, 1602, 1554, 1449, 1409, 1365,1319, 1312, 1302, 1254, 1166, 1113, 762 cm⁻¹; MS (EI) m/z 487 (M⁺), 346,345, 105, 94, 92, 76, 65, 62, 56, 52; MS (FAB) m/z 488 (M+H⁺), 488, 487,434, 433, 432, 431, 388, 57, 42, 41; HRMS (EI) calcd for C₂₅H₂₇Cl₂N₃O₃487.1429, found 487.1441; Anal. Calcd for C₂₅H₂₇Cl₂N₃O₃: C, 61.48; H,5.57; N, 8.60; found: C, 61.41; H, 5.70; N, 8.48.

Example 177

[0817] Preparation of2-(9,10-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-phenylacetamidehydrochloride

[0818] To a solution of tert-butyl6-(2-anilino-2-oxoethyl)-9,10-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(40 mg, 0.082 mmol) in CH₂Cl₂ (3 mL), TFA (0.032 mL, 0.41 mmol) wasadded while stirring at rt. Additional TFA (0.032 mL, 0.41 mmol) wasadded after 3 h. After 69 h, TFA (0.25 mL, 3.2 mmol) was added alongwith additional CH₂Cl₂ (3 mL). The reaction was quenched with 10%aqueous NaOH (5 mL) after 70 h and extracted with CH₂Cl₂ (3×15 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄,decanted, and concentrated to give 30 mg of crude solid. Thehydrochloride salt prepared to give 23 mg (67%) of a white solid: mp274.0-276.0° C.; ¹H NMR (300 MHz, DMSO) δ7.58 (d, J=7.9 Hz, 2H), 7.52(d, J=8.7 Hz, 1H), 7.32 (m, 3H), 7.07 (t, J=7.2 Hz, 1H), 5.14 (s, 2H),3.56 (m, 2H), 3.18 (m, 2H); IR (diffuse reflectance) 2995, 2983, 2967,2948, 2940, 2936, 2809, 2767, 1680, 1600, 1549, 1448, 1314, 797, 759cm⁻¹; MS (ES+) m/z 388 (M+H⁺), 361, 359, 268, 266, 242, 241, 240, 238,228, 226; Anal. Calcd for C₂₀H₁₉Cl₂N₃O.HCl: C, 56.55; H, 4.75; N, 9.89;found: C, 56.25; H, 4.89; N,

[0819] Preparation 79

[0820] Preparation of tert-Butyl9,10-dichloro-6-[2-(4-methoxyanilino)-2-oxoethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0821] DMAP (89 mg, 0.73 mmol), p-anisidine (0.10 g, 0.81 mmol) and DIC(0.13 mL, 0.81 mmol) were added to the solution of crude[3-(tert-butoxycarbonyl)-9,10-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl]aceticacid (0.30 g, 0.73 mmol) in dry THF (3.5 mL). After 4 h, additionalp-anisidine (45 mg, 0.37 mmol) was added. The reaction was diluted withEtOAc after another 17 h and washed with 10% aqueous citric acid (20mL), saturated aqueous NaHCO₃ (20 mL), and brine (20 mL). The organiclayer was then dried over Na₂SO₄, decanted, and concentrated impureproduct. It was then crystallized from EtOAc/heptane, triturated withpentane, and recrystallized from EtOAc/heptane to give 0.14 g (36%) of awhite solid: mp 143.0-144.0° C.; ¹H NMR (300 MHz, DMSO) δ10.30 (s, 1H),7.47 (m, 3H), 7.25 (d, J=8.7 Hz, 1H), 6.88 (d, J=9.0 Hz, 2H), 5.04 (brs, 2H), 3.71 (s, 3H), 3.63 (m, 4H), 3.39 (m, 2H), 2.99 (m, 2H), 1.40(app d, 9H); IR (diffuse reflectance) 2975, 1666, 1545, 1514, 1474,1451, 1414, 1365, 1253, 1239, 1222, 1173, 1158, 830, 784 cm⁻¹; MS (EI)m/z 517 (M⁺), 377, 375, 227, 224, 212, 134, 124, 121, 55, 53; MS (FAB)m/z 518 (M+H⁺), 520, 519, 518, 517, 464, 463, 462, 461, 418, 57; HRMS(EI) calcd for C₂₆H₂₉Cl₂N₃O₄ 517.1535, found 517.1537; Anal. Calcd forC₂₆H₂₉Cl₂N₃O₄: C, 60.24; H, 5.64; N, 8.10; found: C, 59.86; H, 5.68; N,7.94.

Example 178

[0822] Preparation of2-(9,10-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(4-methoxyphenyl)acetamnide hydrochloride

[0823] To a solution of tert-butyl9,10-dichloro-6-[2-(4-methoxyanilino)-2-oxoethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (90 mg, 0.17mmol) in CH₂Cl₂ (6.0 mL), TFA (0.27 mL, 3.5 mmol) was added whilestirring at rt. After 5 h, the reaction was made basic with 10% aqueousNaOH and extracted with CH₂Cl₂ (3×10 mL). The combined organic layerswere washed with brine, dried over Na₂SO₄, decanted, and concentrated to70 mg of a crude white solid. The hydrochloride salt was prepared togive 49 mg (62%) of a white solid: mp 262.0-263.0° C.; ¹H NMR (300 MHz,DMSO) δ10.39 (s, 1H), 9.08 (br s, 2H), 7.50 (m, 3H), 7.30 (d, J=8.7 Hz,1H), 6.89 (d, J=9.1 Hz, 2H), 5.10 (s, 2H), 3.71 (s, 3H), 3.55 (m, 2H),3.19 (m, 2H); ¹³C NMR (400 MHz, DMSO) δ165.2, 155.3, 140.4, 135.6,131.9, 123.9, 122.7, 122.0, 121.4, 120.6, 113.8, 110.6, 110.1, 55.0,46.0, 45.3, 43.5, 22.3, 21.2; IR (diffuse reflectance) 3316, 2950, 2930,2912, 2900, 2803, 2741, 1679, 1532, 1449, 1433, 1414, 1317, 1255, 837cm⁻¹; MS (ES+) m/z 418 (M+H⁺), 391, 389, 266, 241, 240, 240, 238, 228,226, 226; Anal. Calcd for C₂₁H₂₁Cl₂N₃O₂.HCl: C, 55.46; H, 4.88; N, 9.24,found: C, 55.16; H, 4.97; N, 9.06.

[0824] Preparation 80

[0825] Preparation of tert-Butyl9,10-dichloro-6-[2-(2,3-dimethylanilino)-2-oxoethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0826] DMAP (89 mg, 0.73 mmol), 2,3-dimethylaniline (98 mg, 0.81 mmol)and DIC (0.13 mL, 0.81 mmol) were added to the solution of crude[3-(tert-butoxycarbonyl)-9,10-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl]aceticacid (0.30 g, 0.73 mmol) in dry THF (3.5 mL). After 4 h, additional2,3-dimethylaniline (0.049 mL, 0.40 mmol) and THF (2 mL) was added. Thereaction was diluted with EtOAc after 25 h followed by washing with 10%aqueous citric acid (75 mL), saturated aqueous NaHCO₃ (40 mL), and brine(40 mL). A precipitate in the combined organic layers was filtered toyield 0.22 g (58%) white solid: mp 232.5-233.0° C.; ¹H NMR (DMSO, 400MHz) δ9.77 (s, 1H), 7.49 (d, J=8.8 Hz, 1H), 7.28 (d, J=8.7 Hz, 1H), 7.13(d, J=6.8 Hz, 1H), 7.03 (m, 2H), 5.11 (s, 2H), 3.64 (m, 4H), 3.39 (m,2H), 3.03 (m, 2H), 2.24 (s, 3H), 2.09 (s, 3H), 1.41 (s, 9H); IR (diffusereflectance) 2977, 1692, 1659, 1541, 1474, 1451, 1412, 1366, 1303, 1269,1201, 1174, 1112, 791, 773 cm⁻¹; MS (EI) m/z 515 (M⁺), 376, 226, 224,212, 189, 149, 133, 119, 55, 52; HRMS (EI) calcd for C₂₇H₃₁Cl₂N₃O₃515.1743, found 515.1747.

Example 179

[0827] Preparation of2-(9,10-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(2,3-dimethylphenyl)acetamidehydrochloride

[0828] To a solution of tert-butyl9,10-dichloro-6-[2-(2,3-dimethylanilino)-2-oxoethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.15 g, 0.29 mmol) in CH₂Cl₂ (11 mL), TFA (0.45 mL, 5.8 mmol) was addedwhile stirring at rt. After 5 h, the reaction was made basic with 10%aqueous NaOH and extracted with CH₂Cl₂ (7×15 mL). The combined organiclayers were washed with brine, dried over Na₂SO₄, decanted, andconcentrated to give 0.11 g of a crude solid. The hydrochloride salt wasprepared to give 85 mg (65%) of a white solid: mp 248.0-249.5° C.; ¹HNMR (300 MHz, DMSO) δ9.83 (s, 1H), 9.07 (br s, 2H), 7.55 (d, J=8.7 Hz,1H), 7.33 (d, J=8.6 Hz, 1H), 7.12 (m, 1H), 7.03 (m, 2H), 5.17 (s, 2H),3.55 (m, 2H), 3.21 (m, 2H), 2.24 (s, 3H), 2.08 (s, 3H); ¹³C NMR (400MHz, DMSO) δ165.9, 140.4, 137.0, 135.6, 135.3, 130.9, 127.1, 125.1,123.9, 123.2, 122.8, 122.0, 121.4, 110.7, 110.0, 45.8, 45.3, 43.5, 22.3,21.2, 20.0, 14.0; IR (diffuse reflectance) 3301, 2966, 2941, 2916, 2878,2851, 2813, 2767, 2737, 2692, 2633, 2438, 1668, 1534, 1451 cm⁻¹; MS(ES+) m/z 416 (M+H⁺), 389, 389, 387, 266, 242, 240, 238, 228, 226; %Water (KF): 1.99; Anal. Calcd for C₂₂H₂₃Cl₂N₃O.HCl.1.99% H₂O: C, 57.19;H, 5.46; N, 9.10; found: C, 56.97; H, 5.46; N, 8.92.

Examples 180-239

[0829] The compounds of Examples 180-239 were prepared using thefollowing general procedure and the purification technique noted.

[0830] The appropriate aryl amine (0.29 mmol) was added to a 20 mLscintillation vial followed by the addition of a stock solution of theappropriate dichloroazepinoindole acid (5 mL, 0.053 M in THF). Next, astock solution of EEDQ (3 mL, 0.097 M in THF) was added to each vial.The vials were capped, placed in a J-KEM® heater block attached to aLab-Line® orbit shaker and shaken (250 RPM) at 40° C. overnight. Asubset of the reactions was monitored by HPLC. After all the startingacid was consumed in these reactions, MeOH (3 mL) and Dowex® 50WX2-400ion-exchange resin (0.75 g) was added to each vial. The reactions werethen shaken (300 RPM) at 40° C. until the product was on the resin,based on HPLC monitoring. The vials were cooled to rt and transferredwith 2×5 mL of CH₂Cl₂/MeOH (3:1) to disposable fritted syringe barrelson a syringe washing station. The resin was then rinsed with 2×5 mL ofeach of the following: pyridine/MeOH (3:7), CH₂Cl₂, and MeOH. Thesyringe barrels were then transferred to a vacuum manifold and theproduct was eluted off the resin into 40 mL scintillation vials with 5×5mL of MeOH/NH₄OH (3:1). Three different methods were used to isolateproducts.

[0831] Method A consisted of removing the solvent in the vacuum ovenovernight at 47° C.

[0832] Method B involved blowing the solvent down under nitrogen andthen further drying in the vacuum oven overnight at 47° C.

[0833] Method C consisted of filtering the precipitate that formed uponbeing blown down under nitrogen. The products were then evaluated byHPLC and MS or LC/MS.

Example 180

[0834]2-(8,9-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(2,3-dimethylphenyl)acetamide;

[0835] isolation method A; MS (ESI+) m/z 415.9 (MH⁺).

Example 181

[0836]2-(9,10-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(2,3-dimethylphenyl)acetamide;

[0837] isolation method A, the title compound was obtained. MS (ESI+)m/z 415.9 (MH⁺).

Example 182

[0838]2-(7,8-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(2,3-dimethylphenyl)acetamide;

[0839] isolation method C; MS (ESI+) m/z 416.3 (MH⁺).

Example 183

[0840]2-(7,9-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(2,3-dimethylphenyl)acetamide;

[0841] isolation method C; MS (ESI+) m/z 416.1 (MH⁺).

Example 184

[0842]2-(7,10-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(2,3-dimethylphenyl)acetamide;

[0843] isolation method C; MS (ESI+) m/z 416.3 (MH⁺).

Example 185

[0844]2-(8,10-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(2,3-dimethylphenyl)acetamide;

[0845] isolation method C; MS (ESI+) m/z 416.1 (MH⁺).

Example 186

[0846]2-(8,9-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(5,6,7,8-tetrahydro-1-naphthalenyl)acetamide;

[0847] isolation method A; MS (ESI+) m/z 441.9 (MH⁺).

Example 187

[0848]2-(9,10-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(5,6,7,8-tetrahydro-1-naphthalenyl)acetamide;

[0849] isolation method A; MS (ESI+) m/z 441.9 (MH⁺).

Example 188

[0850]2-(7,8-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(5,6,7,8-tetrahydro-1-1-naphthalenyl)acetamide;

[0851] isolation method C; MS (ESI+) m/z 442.1 (MH⁺).

Example 189

[0852]2-(7,9-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(5,6,7,8-tetrahydro-1-naphthalenyl)acetamide;

[0853] isolation method C; MS (ESI+) m/z 442.1 (MH⁺).

Example 190

[0854]2-(7,10-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(5,6,7,8-tetrahydro-1-naphthalenyl)acetamide;

[0855] isolation method C; MS (ESI+) m/z 442.1 (MH⁺).

Example 191

[0856]2-(8,10-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(5,6,7,8-tetrahydro-1-naphthalenyl)acetamide;

[0857] isolation method C; MS (ESI+) m/z 442.1 (MH⁺).

Example 192

[0858]2-(8,9-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(3-ethylphenyl)acetamide;

[0859] isolation method A; MS (ESI+) m/z 415.9 (MH⁺).

Example 193

[0860]2-(9,10-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(3-ethylphenyl)acetamide;

[0861] isolation method A; MS (ESI+) m/z 415.9 (MH⁺).

Example 194

[0862]2-(7,8-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(3-ethylphenyl)acetamide;

[0863] isolation method C; MS (ESI+) m/z 416.4 (MH⁺).

Example 195

[0864]2-(7,9-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(3-ethylphenyl)acetamide;

[0865] isolation method C; MS (ESI+) m/z 416.4 (MH⁺).

Example 196

[0866]2-(7,10-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(3-ethylphenyl)acetamide;

[0867] isolation method C; MS (ESI+) m/z 416.3 (MH⁺).

Example 197

[0868]2-(8,10-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(3-ethylphenyl)acetamide;

[0869] isolation method B; MS (ESI+) m/z 415.9 (MH⁺).

Example 198

[0870]2-(8,9-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(3-isopropylphenyl)acetamide;

[0871] isolation method A; MS (ESI+) m/z 429.9 (MH⁺).

Example 199

[0872]2-(9,10-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(3-isopropylphenyl)acetamide;

[0873] isolation method A; MS (ESI+) m/z 429.9 (MH⁺).

Example 200

[0874]2-(7,8-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(3-isopropylphenyl)acetamide;

[0875] isolation method B; MS (EST+) m/z 429.9 (MH⁺).

Example 201

[0876]2-(7,9-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(3-isopropylphenyl)acetamide;

[0877] isolation method C; MS (ESI+) m/z 430.4 (MH⁺).

Example 202

[0878]2-(7,10-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(3-isopropylphenyl)acetarmide;

[0879] isolation method C; MS (ESI+) m/z 430.4 (MH⁺).

Example 203

[0880]2-(8,10-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(3-isopropylphenyl)acetamide;

[0881] isolation method B; MS (ESI+) m/z 431.9 (MH⁺).

Example 204

[0882]N-(3-tert-Butylphenyl)-2-(8,9-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamide;

[0883] isolation method A; MS (ESI+) m/z 443.9 (MH⁺).

Example 205

[0884]N-(3-tert-Butylphenyl)-2-(9,10-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamide;

[0885] isolation method A; MS (ESI+) m/z 443.9 (MH⁺).

Example 206

[0886]N-(3-tert-Butylphenyl)-2-(7,8-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamide;

[0887] isolation method B; MS (ESI+) m/z 443.9 (MH⁺).

Example 207

[0888]N-(3-tert-Butylphenyl)-2-(7,9-diclhloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetarmde;

[0889] isolation method C; MS (ESI+) m/z 443.9 (MH⁺).

Example 208

[0890] N-(3-tert-Butylphenyl)-2-(7,10-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamide;

[0891] isolation method C; MS (ESI+) m/z 444.4 (MH⁺).

Example 209

[0892]N-(3-tert-Butylphenyl)-2-(8,10-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamide;

[0893] isolation method B; MS (ESI+) m/z 443.9 (MH⁺).

Example 210

[0894]N-(1,3-Benzothiazol-2-yl)-2-(8,9-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamide;

[0895] isolation method A; MS (ESI+) m/z 444.8 (MH⁺).

Example 211

[0896]N-(1,3-Benzothiazol-2-yl)-2-(9,10-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamide;

[0897] isolation method A; MS (ESI+) m/z 444.8 (MH⁺).

Example 212

[0898]N-(1,3-Benzothiazol-2-yl)-2-(7,8-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamide;

[0899] isolation method C; MS (ESI+) m/z 445.1 (MH⁺).

Example 213

[0900]N-(1,3-Benzothiazol-2-yl)-2-(7,9-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamide;

[0901] isolation method C; MS (ESI+) m/z 445.0 (MH⁺).

Example 214

[0902]N-(1,3-Benzothiazol-2-yl)-2-(7,10-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamide;

[0903] isolation method C; MS (ESI+) m/z 445.0 (MH⁺).

Example 215

[0904]N-(1,3-Benzothiazol-2-yl)-2-(8,10-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamide;

[0905] isolation method C; MS (ESI+) m/z 445.3 (MH⁺).

Example 216

[0906]2-(8,9-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(4-methyl-1,3-thiazol-2-yl)acetamide;

[0907] isolation method A; MS (ESI+) m/z 408.9 (MH⁺).

Example 217

[0908]2-(9,10-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(4-methyl-1,3-thiazol-2-yl)acetamide;

[0909] isolation method A; MS (ESI+) m/z 408.9 (MH⁺).

Example 218

[0910]2-(7,8-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(4-methyl-1,3-thiazol-2-yl)acetamide;

[0911] isolation method B; MS (ESI+) m/z 408.9 (MH⁺).

Example 219

[0912]2-(7,9-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(4-methyl-1,3-thiazol-2-yl)acetamide;

[0913] isolation method B; MS (ESI+) m/z 408.9(MH⁺).

Example 220

[0914]2-(7,10-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(4-methyl-1,3-thiazol-2-yl)acetamide;

[0915] isolation method B; MS (ESI+) m/z 408.9 (MH⁺).

Example 221

[0916]2-(8,10-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(4-methyl-1,3-thiazol-2-yl)acetamide;

[0917] isolation method C; MS (ESI+) m/z 408.8 (MH⁺).

Example 222

[0918]2-(8,9-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(5-methyl-1,3-thiazol-2-yl)acetanude;

[0919] isolation method A; MS (ESI+) m/z 408.9 (MH⁺).

Example 223

[0920]2-(9,10-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(5-methyl-1,3-thiazol-2-yl)acetamide;

[0921] isolation method A; MS (ESI+) m/z 408.9 (MH⁺).

Example 224

[0922]2-(7,8-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(5-methyl-1,3-thiazol-2-yl)acetamide;

[0923] isolation method C; MS (ESI+) m/z 409.3 (MH⁺).

Example 225

[0924]2-(7,9-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(5-methyl-1,3-thiazol-2-yl)acetamide;

[0925] isolation method C; MS (ESI+) m/z 409.1 (MH⁺).

Example 226

[0926]2-(7,10-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(5-methyl-1,3-thiazol-2-yl)acetamide;

[0927] isolation method C; MS (ESI+) m/z 409.3 (MH⁺).

Example 227

[0928]2-(8,10-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(5-methyl-1,3-thiazol-2-yl)acetamide;

[0929] isolation method C; MS (ESI+) m/z 408.9 (MH⁺).

Example 228

[0930]N-(4-tert-Butyl-1,3-thiazol-2-yl)-2-(8,9-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetaamide;

[0931] isolation method A; MS (ESI+) m/z 450.9 (MH⁺).

Example 229

[0932] N-(4-tert-Butyl-1,3-thiazol-2-yl)-2-(9,10-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamide;

[0933] isolation method A; MS (ESI+) m/z 450.9 (MH⁺).

Example 230

[0934]N-(4-tert-Butyl-1,3-thiazol-2-yl)-2-(7,8-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamide;

[0935] isolation method C; MS (ESI+) m/z 451.2 (MH⁺).

Example 231

[0936]N-(4-tert-Butyl-1,3-thiazol-2-yl)-2-(7,9-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamide;

[0937] isolation method C; MS (ESI+) m/z 451.1 (MH⁺).

Example 232

[0938]N-(4-tert-Butyl-1,3-thiazol-2-yl)-2-(7,10-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamide;

[0939] isolation method C; MS (ESI+) m/z 450.9 (MH⁺).

Example 233

[0940] N-(4-tert-Butyl-1,3-thiazol-2-yl)-2-(8,10-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamide;

[0941] isolation method C; MS (ESI+) m/z 451.2 (MH⁺).

Example 234

[0942]2-(8,9-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(4-phenyl-1,3-thiazol-2-yl)acetamide;

[0943] isolation method A; MS (ESI+) m/z 470.8 (MH⁺).

Example 235

[0944]2-(9,10-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(4-phenyl-1,3-thiazol-2-yl)acetanide;

[0945] isolation method A; MS (ESI+) m/z 471.0 (MH⁺).

Example 236

[0946]2-(7,8-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(4-phenyl-1,3-thiazol-2-yl)acetamide;

[0947] isolation method C; MS (ESI+) m/z 471.1 (MH⁺).

Example 237

[0948]2-(7,9-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(4-phenyl-1,3-thiazol-2-yl)acetamide;

[0949] isolation method C; MS (ESI+) m/z 471.1 (MH⁺).

Example 238

[0950]2-(7,10-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(11H)-yl)-N-(4-phenyl-1,3-thiazol-2-yl)acetamide;

[0951] isolation method C; MS (ESI+) m/z 471.1 (MH⁺).

Example 239

[0952]2-(8,10-Dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(4-phenyl-1,3-thiazol-2-yl)acetamide;

[0953] isolation method C; MS (ESI+) m/z 471.2 (MH⁺)

[0954] Preparation 81

[0955] Preparation of tert-Butyl8,9-dichloro-6-(3-phenylpropyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0956] Potassium hydride (45 mg, 1.1 mmol) was added to a solution oftert-butyl8,9-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.20 g, 0.56 mmol) in DMF (1.0 mL). After 15 min,1-bromo-3-phenylpropane (0.13 mL, 0.86 mmol) was added. After 5 h, thereaction was quenched with saturated aqueous NH₄Cl (10 mL) and extractedwith CH₂Cl₂ (3×10 mL). The combined organic extracts were washed withbrine, dried over Na₂SO₄, decanted, and concentrated. The crude productwas purified by column chromatography (Biotage, 40S) with heptane/EtOAc(3:1) to give 0.21 g (78%) of a yellow solid: mp 119-124° C.; IR(diffuse reflectance) 2980, 2973, 2941, 2932, 1686, 1478, 1462, 1417,1365, 1247, 1178, 1160, 1112, 855, 699 cm⁻¹; MS (EI) m/z 472 (M⁺), 416,227, 226, 224, 211, 188, 153, 115, 90, 56; Anal. Calcd forC₂₆H₃₀Cl₂N₂O₂: C, 65.96; H, 6.39; N, 5.92; found: C, 66.01; H, 6.47; N,5.82.

Example 240

[0957] Preparation of8,9-Dichloro-6-(3-phenylpropyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0958] To a solution of tert-butyl8,9-dichloro-6-(3-phenylpropyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.20 g, 0.42 mmol) in CH₂Cl₂ (5 mL), TFA (0.65 mL, 8.4 mmol) was addedwhile stirring at rt. After 4 h, the reaction was made basic with 10%aqueous NaOH, then extracted with CH₂Cl₂ (3×15 mL). The combined organiclayers were washed with brine, dried over Na₂SO₄, decanted, andconcentrated to 0.12 g of crude material. After the hydrochloride saltwas prepared, it was further purified by recrystallization fromMeOH/EtOAc to give 99 mg (57%) of a white solid: mp 148.0-150.5° C.; ¹HNMR (300 MHz, DMSO) δ9.26 (br s, 2H), 7.75 (d, J=8.7 Hz, 2H), 7.28 (m,2H), 7.20 (m, 3H), 4.19 (m, 2H), 3.19 (m, 2H), 3.08 (m, 2H), 2.61 (m,2H), (pentet, J=7.5 Hz, 2H); ¹³C NMR (400 MHz, DMSO) δ141.0, 138.4,134.0, 128.2, 128.1, 126.5, 125.8, 123.0, 121.4, 118.7, 111.3, 110.2,45.8, 44.0, 42.3, 31.9, 31.5, 22.5, 20.2; IR (diffuse reflectance) 3021,2997, 2970, 2953, 2888, 2850, 2825, 2812, 2760, 2709, 2632, 1473, 1421,1106, 700 cm⁻¹; MS (EI) m/z 374, 372 (M⁺), 332, 331, 330, 228, 226, 91,86, 84.

[0959] Preparation 82

[0960] Preparation of tert-Butyl9,10-dichloro-6-(3-phenylpropyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0961] To a solution of tert-butyl9,10-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.40 g, 1.1 mmol) in DMF (6 mL), sodium hydride (60% dispersion inmineral oil, 68 mg, 1.7 mmol) was added. After 25 min, 1-bromo-3-phenylpropane (0.34 mL, 2.3 mmol) was added. The reaction was quenched withsaturated aqueous NH₄Cl after 3 h and extracted with EtOAc (3×15 mL).The combined organic extracts were washed with brine, dried over Na₂SO₄,decanted, and concentrated. The crude product was purified by columnchromatography (Biotage, 40M) with heptane/EtOAc (17:3) to give 0.33 g(62%) of a yellow solid: mp 113.5-115.5° C.; ¹H NMR (300 MHz, CDCl₃)δ7.14 (m, 3H), 6.93 (d, J=8.7 Hz, 1H), 4.02 (m, 2H), 3.70 (m, 4H), 3.50(m, 2H), 2.93 (m, 2H), 2.65 (t, J=7.5 Hz, 2H), 1.99 (m, 2H), 1.48 (s,9H); IR (diffuse reflectance) 2976, 1686, 1447, 1416, 1366, 1360, 1247,1180, 1168, 1152, 1108, 930, 788, 747, 701 cm⁻¹; MS (FAB) m/z 473(M+H⁺), 475, 474, 473, 472, 419, 418, 417, 416, 91, 57; HRMS (FAB) calcdfor C₂₆H₃₀Cl₂N₂O₂+H 473.1762, found 473.1759; Anal. Calcd forC₂₆H₃₀Cl₂N₂O₂: C, 65.96; H, 6.39; N, 5.92, found: C, 66.00; H, 6.41; N,5.85.

Example 241

[0962] Preparation of9,10-Dichloro-6-(3-phenylpropyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0963] To a solution of tert-butyl9,10-dichloro-6-(3-phenylpropyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.20 g, 0.42 mmol) in CH₂Cl₂ (10 mL), TFA (0.65 mL, 8.4 mmol) was addedwhile stirring at rt. After 5 h, the reaction was made basic with 10%aqueous NaOH, then extracted with CH₂Cl₂ (3×15 mL). The combined organiclayers were washed with brine, dried over Na₂SO₄, decanted, andconcentrated to 0.15 g of a crude solid. After the hydrochloride saltwas prepared, it was further purified by a recrystallization fromMeOH/EtOAc to give 47 mg (27%) of a white solid: mp 214.0-216.0; ¹H NMR(300 MHz, DMSO) δ9.29 (br s, 2H), 7.45 (d, J=8.8 Hz, 1H), 7.27 (m, 3H),7.19 (m, 3H), 4.22 (t, J=7.2 Hz, 2H), 3.51 (m, 2H), 3.22 (m, 2H), 2.61(m, 2H), 1.90 (pentet, J=7.5 Hz, 2H); ¹³C NMR (400 MHz, DMSO) δ141.0,139.2, 134.8, 128.2, 128.0, 125.8, 123.6, 122.4, 121.8, 121.4, 110.5,110.2, 45.1, 43.4, 42.3, 32.0, 31.4, 21.9, 21.1; IR (diffusereflectance) 2972, 2951, 2885, 2824, 2796, 2747, 2722, 2671, 2652, 2443,1448, 1423, 779, 746, 700 cm⁻¹; MS (ES+) m/z 373 (M+H⁺), 344, 232, 232,228, 226, 205, 203, 191, 68; Anal. Calcd for C₂₁H₂₂Cl₂N₂.HCl.2.15% H₂O :C, 60.23; H, 5.78; N, 6.69, found: C, 60.37; H 5.68; N, 6.66.

[0964] Preparation 83

[0965] Preparation of tert-Butyl8,9-dichloro-6-(2-phenoxyethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0966] To a solution of tert-butyl8,9-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.40 g, 1.1 mmol) in DMF (5 mL), sodium hydride (60% dispersion inmineral oil, 68 mg, 1.7 mmol) was added. After 20 min, β-bromophenetole(0.31 mL, 2.3 mmol) was added. The reaction was quenched with saturatedaqueous NH₄Cl after 2 h and extracted with EtOAc (3×15 mL). The combinedorganic extracts were washed with brine, dried over Na₂SO₄, decanted,and concentrated. The crude product was purified by two columnchromatographies (Biotage, 40S) with heptane/EtOAc (17:3) and (Biotage,40M) with heptane/EtOAc (9:1) to give 0.41 g (76%) of a white solid: mp135.5-137.5° C.; ¹H NMR (300 MHz, CDCl₃) δ7.50 (d, J=4.5 Hz, 1H), 7.41(d, J=7.5 Hz, 1H), 6.93 (m, 1H), 6.77 (d, J=7.9 Hz, 2H), 4.42 (m, 2H),4.17 (t, J=5.3 Hz, 2H), 3.70 (m, 4H), 3.09 (m, 2H), 2.89 (m, 2H), 1.49(s, 9H); IR (diffuse reflectance) 1678, 1494, 1469, 1406, 1364, 1297,1245, 1233, 1172, 1119, 1106, 941, 875, 758, 691 cm⁻¹; MS (ES+) m/z 475(M+H⁺), 498, 497, 348, 346, 255, 252, 169, 137, 121, 90; Anal. Calcd forC₂₅H₂₈Cl₂N₂O₃: C, 63.16; H, 5.94; N, 5.89; found: C, 63.22; H, 6.00; N,5.88.

Example 242

[0967] Preparation of8,9-Dichloro-6-(2-phenoxyethyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0968] To a solution of tert-butyl8,9-dichloro-6-(2-phenoxyethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.20 g, 0.42 mmol) in CH₂Cl₂ (5 mL), TFA (0.65 mL, 8.5 mmol) was addedwhile stirring at rt. After 3 h, the reaction was made basic with 10%aqueous NaOH and extracted with CH₂Cl₂ (3×15 mL). The combined organiclayers were washed with brine, dried over Na₂SO₄, decanted, andconcentrated to give 0.18 g of a crude solid. The hydrochloride salt wasprepared to give 0.13 g (73%) of an off-white solid: mp 235.0-235.5° C.;¹H NMR (300 MHz, DMSO) 8 9.20 (br s, 2H), 7.88 (s, 1H), 7.76 (s, 1H),7.25 (m, 2H), 6.91 (t, J=7.2 Hz, 1H), 6.83 (d, J=7.5 Hz, 2H), 4.61 (m,2H), 4.17 (t, J=4.5 Hz, 2H), 3.09 (m, 2H); ¹³C NMR (400 MHz, DMSO)δ157.8, 139.3, 134.2, 129.4, 126.7, 123.0, 121.6, 120.7, 118.7, 114.1,111.8, 110.3, 66.7, 45.8, 44.2, 42.2, 22.9, 20.2; IR (diffusereflectance) 2949, 2934, 2740, 2697, 2678, 1592, 1495, 1468, 1244, 1108,886, 877, 754, 745, 687 cm⁻¹; MS (EI) m/z 376, 374 (M⁺), 334, 333, 332,119, 91, 77, 65, 51; Anal. Calcd for C₂₀H₂₀Cl₂N₂O.HCl: C, 58.34; H,5.14; N, 6.80; found: C, 57.99; H, 5.23; N, 6.66.

[0969] Preparation 84

[0970] Preparation of tert-Butyl8,9-dichloro-6-[2-(4-chlorophenoxy)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0971] To a solution of tert-butyl8,9-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.40 g, 1.1 mmol) in DMF (5 mL), sodium hydride (60% dispersion inmineral oil, 68 mg, 1.7 mmol) was added. After 20 min, 2-chlorophenyl2-bromoethyl ether (0.34 mL, 2.3 mmol) was added. The reaction wasquenched with saturated aqueous NH₄Cl after 3 h and extracted with EtOAc(3×15 mL). The combined organic extracts were washed with brine, driedover Na₂SO₄, decanted, and concentrated. The crude product was purifiedby column chromatography (Biotage, 40M) with heptane/EtOAc (17:3) togive 0.47 g (82%) of a white foam: ¹H NMR (300 MHz, CDCl₃) δ7.50 (d,J=4.5 Hz, 1H), 7.40 (d, J=6.0 Hz, 1H), 7.18 (d, J=9.0 Hz, 2H), 6.68 (m,2H), 4.40 (t, J=5.3 Hz, 2H), 4.16 (t, J=5.3 Hz, 2H), 3.64 (m, 4H), 3.06(m, 2H), 2.90 (m, 2H), 148 (s, 9H); IR (diffuse reflectance) 1691, 1687,1491, 1467, 1413, 1365, 1297, 1285, 1268, 1242, 1221, 1169, 1114, 1104,822 cm⁻¹; MS (ES+) m/z 509 (M+H⁺), 533, 531, 392, 292, 160, 155, 146,118, 106, 91; Anal. Calcd for C₂₅H₂₇Cl₃N₂O₃: C, 58.89; H, 5.34; N, 5.49,found: C, 58.89; H, 5.44; N, 5.48.

Example 243

[0972] Preparation of8,9-Dichloro-6-[2-(4-chlorophenoxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0973] To a solution of tert-butyl8,9-dichloro-6-[2-(4-chlorophenoxy)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.30 g, 0.59 mmol) in CH₂Cl₂ (10.0 mL), TFA (0.91 mL, 12 mmol) wasadded while stirring at rt. After 3 h, the reaction was made basic with10% aqueous NaOH and extracted with CH₂Cl₂ (3×15 mL). The combinedorganic layers were washed with brine, dried over Na₂SO₄, decanted, andconcentrated to give 0.24 g of crude material. The hydrochloride saltwas prepared to give 0.21 g (82%) of an off-white solid: mp 262.3-263.5°C.; ¹H NMR (300 MHz, DMSO) δ9.27 (br s, 2H), 7.86 (s, 1H), 7.76 (s, 1H),7.30 (d, J=8.9 Hz, 2H), 6.86 (t, J=8.9 Hz, 2H), 4.61 (t, J=4.5 Hz, 2H),4.17 (m, 2H), 3.08 (m, 2H); ¹³C NMR (400 MHz, DMSO) δ156.8, 139.3,134.2, 129.2, 126.7, 124.5, 123.1, 121.7, 118.7, 116.0, 111.8, 110.3,67.2, 45.9, 44.2, 42.1, 22.9, 20.3; IR (diffuse reflectance) 2949, 2823,2757, 2715, 2703, 2676, 1589, 1491, 1472, 1324, 1243, 1110, 868, 814,666 cm⁻¹; MS (EI) m/z 408 (M⁺), 111, 99, 86, 84, 78, 73, 63, 57, 51, 50;Anal. Calcd for C₂₀H₁₉Cl₃N₂O.HCl: C, 53.84; H, 4.52; N, 6.28, found: C,53.47; H, 4.56; N, 6.17.

[0974] Preparation 85

[0975] Preparation of tert-Butyl8,9-dichloro-6-[2-(4-fluorophenoxy)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0976] To a solution of tert-butyl8,9-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.40 g, 1.1 mmol) in DMF (5 mL), sodium hydride (60% dispersion inmineral oil, 68 mg, 1.7 mmol) was added. After 25 min, 4-fluorophenoxyethyl bromide (0.34 mL, 2.3 mmol) was added. The reaction was quenchedwith saturated aqueous NH₄Cl after 2 h and extracted with EtOAc (3×15mL). The combined organic extracts were washed with brine, dried overNa₂SO₄, decanted, and concentrated. The crude product was purified bycolumn chromatography (Biotage, 40M) with heptane/EtOAc (gradient, 9:1to 17:3) to give 0.43 g (78%) of a white foam: ¹H NMR (300 MHz, CDCl₃)δ7.51 (d, J=3.8 Hz, 1H), 7.40 (d, J=6.0 Hz, 1H), 6.92 (t, J=8.7 Hz, 2H),6.70 (m, 2H), 4.40 (t, J=5.3 Hz, 2H), 4.13 (t, J=5.3 Hz, 4H), 3.69 (m,4H), 3.08 (m, 2H), 2.90 (m, 2H), 1.48 (s, 9H); IR (diffuse reflectance)1687, 1505, 1468, 1414, 1366, 1296, 1268, 1248, 1218, 1169, 1114, 1105,865, 827, 746 cm⁻¹; MS (ES+) m/z 493 (M+H⁺), 516, 515, 366, 364, 265,253, 138, 94, 91, 85; Anal. Calcd for C₂₅H₂₇Cl₂FN₂O₃: C, 60.86; H, 5.51;N, 5.68, found: C, 60.91; H, 5.61; N, 5.64.

Example 244

[0977] Preparation of8,9-Dichloro-6-[2-(4-fluorophenoxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0978] To a solution of tert-butyl8,9-dichloro-6-[2-(4-fluorophenoxy)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.20 g, 0.41 mmol) in CH₂Cl₂ (5.0 mL), TFA (0.63 mL, 8.1 mmol) wasadded while stirring at rt. After 5 h, the reaction was made basic with10% aqueous NaOH, then extracted with CH₂Cl₂ (3×15 mL). The combinedorganic layers were washed with brine, dried over Na₂SO₄, decanted, andconcentrated to 0.17 g of crude material. The hydrochloride salt wasprepared to give 0.16 g (93%) of an off-white solid: mp 189.5-192.0° C.;¹H NMR (300 MHz, DMSO) δ9.19 (br s, 2H), 7.86 (s, 1H), 7.77 (s, 1H),7.09 (m, 2H), 6.84 (m, 2H), 4.60 (t, J=4.9 Hz, 2H), 4.15 (t, J=4.9 Hz,2H), 3.09 (m, 2H); ¹³C NMR (400 MHz, DMSO) δ157.6, 155.3, 154.1, 139.3,134.2, 126.7, 123.0, 121.6, 118.7, 115.9, 115.6, 115.4, 115.3, 111.8,110.3, 67.3, 45.8, 44.2, 42.2, 22.9, 20.2; IR (diffuse reflectance)2950, 2937, 2834, 2757, 2741, 2664, 1508, 1466, 1246, 1225, 1208, 8719,826, 816, 747 cm⁻¹; MS (ES+) mlZ 393 (M+H⁺), 366, 255, 238, 211, 191,170, 168, 147, 74, 72; % Water (KF): 1.36; Anal. Calcd forC₂₀H₁₉Cl₂FN₂O.HCl.36% H₂O : C, 55.14; H, 4.78; N, 6.43, found: C, 54.83;H, 4.88; N, 6.30.

[0979] Preparation 86

[0980] Preparation of tert-Butyl9,10-dichloro-6-(2-phenoxyethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0981] To a solution of tert-butyl9,10-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.20 g, 0.56 mmol) in DMF (4 mL), sodium hydride (60% dispersion inmineral oil, 34 mg, 0.84 mmol) was added. After 25 min, β-bromophenetole(0.15 mL, 1.1 mmol) was added. The reaction was quenched with saturatedaqueous NH₄Cl after 2 h and extracted with EtOAc (3×15 mL). The combinedorganic extracts were washed with brine, dried over Na₂SO₄, decanted,and concentrated. The crude product was purified by columnchromatography (Biotage, 40S) with heptane/EtOAc (17:3) and trituratingwith hexanes gave 35 mg (13%) of a white solid: mp 175.0-176.0° C.; ¹HNMR (400 MHz, DMSO) δ7.53 (d, J=8.8 Hz, 1H), 7.24 (m, 3H), 6.90 (t,J=7.6 Hz, 1H), 6.81 (d, J=7.6 Hz, 1H), 6.81 (d, J=7.9 Hz, 2H), 4.60 (m,2H), 4.17 (m, 2H), 3.67 (m, 2H), 3.61 (m, 2H), 3.14 (t, J=5.3 Hz, 2H),1.41 (s, 9H); IR (diffuse reflectance) 2967, 2931, 1676, 1493, 1448,1422, 1406, 1363, 1298, 1245, 1221, 1167, 1118, 754, 690 cm⁻¹; MS (EI)m/z 474 (M⁺), 333, 95, 92, 79, 78, 76, 67, 64, 57, 55; HRMS (FAB) calcdfor C₂₅H₂₈Cl₂N₂O₃+H 475.1555, found 475.1559; Anal. Calcd forC₂₅H₂₈Cl₂N₂O₃: C, 63.16; H, 5.94; N, 5.89; found: C, 63.47; H, 6.11; N,5.84.

Example 245

[0982] Preparation of9,10-Dichloro-6-(2-phenoxyethyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0983] TFA (0.39 mL, 5.1 mmol) was added to a solution of tert-butyl9,10-dichloro-6-(2-phenoxyethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.12 g, 0.25 mmol) in CH₂Cl₂ (6.0 mL). After 4.5 h, the reaction wasmade basic with 10% aqueous NaOH and extracted with CH₂Cl₂ (3×10 mL).The combined organic layers were washed with brine, dried over Na₂SO₄,decanted, and concentrated to 90 mg of a light yellow crude oil. Thehydrochloride salt was prepared to give 61 mg (59%) of a white solid: mp194.0-196.5° C.; ¹H NMR (300 MHz, DMSO) δ9.17 (br s, 2H), 7.59 (d, J=8.8Hz, 1H), 7.28 (m, 3H), 6.91 (t, J=7.3 Hz, 1H), 6.83 (d, J=7.9 Hz, 2H),4.63 (t, J=4.7 Hz, 2H), 4.17 (t, J=4.9 Hz, 2H), 3.53 (m, 2H); ¹³C NMR(400 MHz, DMSO) δ157.8, 140.1, 135.0, 129.4, 123.8, 122.7, 121.9, 121.3,120.8, 114.1, 110.6, 66.5, 45.1, 43.6, 42.3, 22.3, 21.2; IR (diffusereflectance) 2979, 2955, 2867, 2824, 2797, 2757, 2730, 2673, 2656, 1495,1459, 1442, 1240, 1221, 758 cm⁻¹; MS (ES+) m/z 375 (M+H⁺), 348, 346,346, 255, 253, 240, 238, 227, 225, 121; % Water (KF): 2.99; Anal. Calcdfor C₂₀H₂₀Cl₂N₂O.HCl.2.99% H₂O: C, 56.60; H, 5.32; N, 6.60; found: C,56.53; H, 5.64; N, 6.53.

[0984] Preparation 87

[0985] Preparation of tert-Butyl9,10-dichloro-6-[2-(4-chlorophenoxy)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0986] Sodium hydride (60% dispersion in mineral oil, 68 mg, 1.7 mmol)was added to a solution of tert-butyl9,10-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.40 g, 1.1 mmol) in DMF (6 mL). After 25 min, 2-chlorophenyl2-bromoethyl ether (0.34 mL, 2.3 mmol) was added. The reaction wasquenched with saturated aqueous NH₄Cl after 19 h and extracted withEtOAc (3×20 mL). The combined organic extracts were washed with brine,dried over Na₂SO₄, decanted, and concentrated. The crude product waspurified by column chromatography (Biotage, 40M) with heptane/EtOAc(17:3) to give 0.46 g (76%) of a white foam: ¹H NMR (300 MHz, CDCl₃)δ7.17 (m, 4H), 6.68 (d, J=9.0 Hz, 2H), 4.45 (t, J=5.3 Hz, 2H), 4.13 (t,J=3.5 Hz, 2H), 3.72 (m, 4H), 3.51 (m, 2H), 3.11 (m, 2H), 1.48 (s, 9H);IR (diffuse reflectance) 2975, 2930, 1691, 1492, 1448, 1414, 1392, 1365,1300, 1285, 1269, 1244, 1169, 1114, 823 cm⁻¹; MS (FAB) m/z 509 (M+H⁺),510, 509, 508, 455, 454, 453, 452, 57, 42, 41; HRMS (EI) calcd forC₂₅H₂₇Cl₃N₂O₃ 508.1087, found 508.1089; Anal. Calcd for C₂₅H₂₇Cl₃N₂O₃:C, 58.89; H, 5.34; N, 5.49; found: C, 58.94; H, 5.38; N, 5.41.

Example 246

[0987] Preparation of9,10-Dichloro-6-[2-(4-chlorophenoxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0988] TFA (0.84 mL, 11 mmol) was added to a solution of tert-butyl9,10-dichloro-6-[2-(4-chlorophenoxy)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.30 g, 0.55 mmol) in CH₂Cl₂ (10.0 mL). After 3 h, the reaction wasmade basic with 10% aqueous NaOH and CH₂Cl₂ was added to dissolve thepink precipitate that had formed. The layers were separated and theaqueous layer was extracted with additional CH₂Cl₂. The combined organiclayers were washed with brine, dried over Na₂SO₄, decanted, andconcentrated to 0.27 g of a crude solid. The hydrochloride salt wasprepared to give 0.19 g (80%) of a white solid: mp 203.5-205.0; ¹H NMR(300 MHz, DMSO) δ9.32 (br s, 2H), 7.58 (d, J=8.8 Hz, 1H), 7.30 (m, 3H),6.86 (d, J=9.0 Hz, 2H), 4.63 (t, J=4.9 Hz, 2H), 4.17 (m, 2H), 3.52 (m,2H); ¹³C NMR (400 MHz, DMSO) δ156.6, 140.1, 135.0, 129.1, 124.5, 123.8,122.7, 121.9, 121.3, 115.9, 110.7, 110.6, 67.1, 45.1, 43.5, 42.2, 22.2,21.1; IR (diffuse reflectance) 2977, 2953, 2823, 2796, 2749, 2727, 2672,2653, 2442, 1491, 1460, 1442, 1242, 826, 774 cm⁻¹; MS (ES+) m/z 409(M+H⁺), 253, 225, 217, 169, 169, 137, 123, 97, 84, 74; % Water (KF):1.48; Anal. Calcd for C₂₀H₁₉Cl₃N₂O.HCl.1.48% H₂O: C, 53.04; H, 4.62; N,6.19, found: C, 52.90; H, 4.64; N, 6.12.

[0989] Preparation 88

[0990] Preparation of tert-Butyl9,10-dichloro-6-[2-(4-fluorophenoxy)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0991] Sodium hydride (60% dispersion in mineral oil, 68 mg, 1.7 mmol)was added to a solution of tert-butyl9,10-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.40 g, 1.1 mmol) in DMF (6 mL). After 25 min, 4-fluorophenoxy ethylbromide (0.34 mL, 2.3 mmol) was added. The reaction was quenched withsaturated aqueous NH₄Cl after 22 h and extracted with EtOAc (3×15 mL).The combined organic extracts were washed with brine, dried over Na₂SO₄,decanted, and concentrated. The crude product was purified by columnchromatography (Biotage, 40M) with heptane/EtOAc (17:3) to give 0.46 g(82%) of a white solid: mp 163.5-165.5° C.; ¹H NMR (300 MHz, CDCl₃)δ7.16 (m, 2H), 6.92 (m, 2H), 6.70 (m, 2H), 4.44 (m, 2H), 4.12 (m, 2H),3.73 (m, 4H), 3.51 (m, 2H), 3.12 (m, 2H), 1.48 (s, 9H); IR (diffusereflectance) 1675, 1507, 1449, 1405, 1365, 1354, 1298, 1249, 1242, 1221,1209, 1170, 1120, 835, 828 cm⁻¹; MS (FAB) m/z 493 (M+H⁺), 494, 493, 492,439, 438, 437, 436, 435, 57,42; HRMS (EI) calcd for C₂₅H₂₇Cl₂FN₂O₃492.1383, found 492.1385; Anal. Calcd for C₂₅H₂₇Cl₂FN₂O₃: C, 60.86; H,5.51; N, 5.68, found: C, 60.93; H, 5.60; N, 5.69.

Example 247

[0992] Preparation of9,10-Dichloro-6-[2-(4-fluorophenoxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0993] To a solution of tert-butyl9,10-dichloro-6-[2-(4-fluorophenoxy)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.20 g, 0.41 mmol) in CH₂Cl₂ (6.0 mL), TFA (0.63 mL, 8.1 minol) wasadded while stirring at rt. After 30 min, the reaction was made basicwith 10% aqueous NaOH, then extracted with CH₂Cl₂ (3×15 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄,decanted, and concentrated to 0.17 g of a crude solid. After thehydrochloride salt was prepared, it was further purified by arecrystallization from MeOH/EtOAc to give 69 mg (40%) of a white solid:mp 214.0-216.0; ¹H NMR (300 MHz, DMSO) δ7.58 (d, J=8.7 Hz, 1H), 7.31 (d,J=9.0 Hz, 1H), 7.09 (m, 2H), 6.84 (m, 2H), 4.63 (m, 2H), 4.15 (t, J=4.9Hz, 2H), 3.53 (m, 2H), ¹³C NMR (400 MHz, DMSO) δ157.0, 154.7, 153.5,153.5, 139.5, 134.4, 123.2, 122.0, 121.2, 120.7, 115.2, 115.0, 114.8,114.7, 110.0, 109.9, 66.6, 44.5, 42.9, 41.6, 21.6, 20.5; IR (diffusereflectance) 2965, 2838, 2823, 2794, 2770, 2745, 2714, 2697, 2651, 1506,1442, 1249, 1222, 1206, 831 cm⁻¹; MS (ES+) m/z 393 (M+H⁺), 364, 238,221, 175, 79, 74, 66, 64, 62, 61. Anal. Calcd for C₂₀H₁₉Cl₂FN₂O.HCl: C,55.90; H, 4.69; N, 6.52, found: C, 55.65; H, 4.72; N, 6.49.

[0994] Preparation 89

[0995] Preparation of tert-Butyl7,8-dichloro-6-(2-phenoxyethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[0996] Sodium hydride (60% dispersion in mineral oil, 51 mg, 1.3 mmol)was added to a solution of tert-butyl7,8-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.30 g, 0.84 mmol) in DMF (5 mL). After 30 min, β-bromophenetole wasadded (0.31 mL). The reaction was quenched with saturated aqueous NH₄Clafter 18 h and extracted with EtOAc (3×15 mL). The combined organicextracts were washed with brine, dried over Na₂SO₄, decanted, andconcentrated. The crude product was purified by column chromatography(Biotage, 40S) with heptane/EtOAc (17:3) to give 0.22 g (55%) of a whitesolid: mp 138.4-139.7° C.; ¹H NMR (300 MHz, CDCl₃) δ6.92 (m, 1H), 6.79(m, 2H), 4.90 (m, 2H), 4.27 (m, 2H), 3.80 (m, 2H), 3.66 (m, 2H), 3.17(m, 2H), 2.93 (m, 2H), 1.49 (s, 9H); IR (diffuse reflectance) 2979,1687, 1467, 1443, 1416, 1365, 1253, 1239, 1223, 1172, 1165, 1156, 923,808, 760 cm⁻¹; MS (EI) m/z 474 (M⁺), 420, 418, 332, 86, 84, 57, 56, 55,51; Anal. Calcd for C₂₅H₂₈Cl₂N₂O₃: C, 63.16; H, 5.94; N, 5.89; found: C,63.15; H, 6.00; N, 5.89.

Example 248

[0997] Preparation of7,8-Dichloro-6-(2-phenoxyethyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[0998] TFA (0.41 mL, 5.3 mmol) was added to a solution of tert-butyl7,8-dichloro-6-(2-phenoxyethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.13 g, 0.26 mmol) in CH₂Cl₂ (5 mL). After 4 h, the reaction was madebasic with 10% aqueous NaOH and extracted with CH₂Cl₂ (3×15 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄,decanted, and concentrated to give a crude solid. The hydrochloride saltwas prepared to give 61 mg (57%) of a white solid: mp 196.5-197.0° C.;¹H NMR (300 MHz, DMSO) δ9.11 (br s, 2H), 7.49 (d, J=8.5 Hz, 1H), 7.26(m, 3H), 6.90 (m, 3H), 4.95 (m, 2H), 4.26 (m, 2H), 3.09 (m, 2H); ¹³C NMR(300 MHz, DMSO) δ157.8, 139.9, 130.7, 129.4, 128.7, 125.2, 121.0, 120.8,117.5, 114.2, 113.5, 111.5, 67.8, 45.6, 44.0, 43.2, 23.0, 19.9; IR(diffuse reflectance) 2971, 2955, 2828, 2799, 2759, 2677, 2659, 2446,1601, 1588, 1496, 1463, 1244, 811, 760 cm⁻¹; MS (EI) m/z 374 (M⁺), 86,84, 78, 77, 65, 64, 63, 62, 61, 51; Anal. Calcd for C₂₀H₂₀Cl₂N₂O.HCl: C,58.34; H, 5.14; N, 6.80; found: C, 58.12; H, 5.42; N, 6.47.

[0999] Preparation 90

[1000] Preparation of tert-Butyl7,9-dichloro-6-(2-phenoxyethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[1001] Sodium hydride (60% dispersion in mineral oil, 51 mg, 1.3 mmol)was added to a solution of tert-butyl7,9-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.30 g, 0.84 mmol) in DMF (5 mL). After 30 min, β-bromophenetole wasadded (0.23 mL). The reaction was quenched with saturated aqueous NH₄Clafter 18 h and extracted with EtOAc (1×50 mL, 2×20 mL). The combinedorganic extracts were washed with brine, dried over Na₂SO₄, decanted,and concentrated. The crude product was purified by columnchromatography (Biotage, 40S) with heptane/EtOAc (17:3) and crystallizedfrom EtOAc/heptane to give 0.31 g (77%) of a white solid: mp154.0-155.0° C.; ¹H NMR (300 MHz, DMSO) δ7.54 (d, J=1.9 Hz, 1H), 7.20(m, 3H), 6.85 (m, 3H), 4.86 (m, 2H), 4.24 (m, 2H), 3.69 (m, 2H), 3.54(m, 2H), 3.12 (m, 2H), 2.91 (m, 2H), 1.42 (s, 9H); IR (diffusereflectance) 1683, 1463, 1410, 1366, 1345, 1293, 1242, 1232, 1227, 1174,1167, 1113, 857, 756, 693 cm⁻¹; MS (EI) m/z 474 (M⁺), 474, 420, 419,418, 334, 332, 311, 238, 84, 57; Anal. Calcd for C₂₅H₂₈Cl₂N₂O₃: C,63.16; H, 5.94; N, 5.89; found: C, 63.19; H, 5.97; N, 5.86.

Example 249

[1002] Preparation of7,9-Dichloro-6-(2-phenoxyethyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[1003] To a solution of tert-butyl7,9-dichloro-6-(2-phenoxyethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.20 g, 0.42 mmol) in CH₂Cl₂ (6 mL), TFA (0.65 mL, 8.4 mmol) was addedwhile stirring at rt. After 5 h, the reaction was made basic with 10%aqueous NaOH and extracted with CH₂Cl₂ (3×15 mL). The combined organiclayers were washed with brine, dried over Na₂SO₄, decanted, andconcentrated to give a crude solid. The hydrochloride salt was preparedto give 0.10 g (60%) of a white solid: mp 204.0-204.5° C.; ¹H NMR (300MHz, DMSO) δ9.35 (br s, 2H), 7.60 (d, J=1.9 Hz, 1H), 7.26 (m, 3H), 6.90(m, 3H), 4.91 (m, 2H), 4.25 (m, 2H), 3.10 (m, 2H) ¹³C NMR (300 MHz,DMSO) δ157.9, 141.0, 130.9, 129.5, 128.7, 123.7, 122.1, 120.9, 116.5,115.9, 114.2, 111.5, 67.8, 45.6, 44.0, 43.2, 22.9, 20.0; IR (diffusereflectance) 2969, 2941, 2924, 2847, 2832, 2809, 2734, 2691, 2664, 2632,2430, 1493, 1464, 1250, 767 cm⁻¹; MS (EI) m/z 374 (M⁺), 334, 332, 238,224, 188, 94, 77, 65, 51; Anal. Calcd for C₂₀H₂₀Cl₂N₂O.HCl: C, 58.34; H,5.14; N, 6.80; found: C, 58.15; H, 5.19; N, 6.72.

[1004] Preparation 91

[1005] Preparation of tert-Butyl7,10-dichloro-6-(2-phenoxyethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[1006] Sodium hydride (60% dispersion in mineral oil, 51 mg, 1.3 mmol)was added to a solution of tert-butyl7,10-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.30 g, 0.84 mmol) in DMF (5 mL). After 25 min, β-bromophenetole wasadded (0.23 mL). The reaction was quenched with saturated aqueous NH₄Clafter 18 h and extracted with EtOAc (3×20 mL). The combined organicextracts were washed with brine, dried over Na₂SO₄, decanted, andconcentrated. The crude product was purified by column chromatography(Biotage, 40S) with heptane/EtOAc (9:1) to give 0.32 g (79%) of a whitesolid: mp 131.5-133.0° C.; ¹H NMR (300 MHz, CDCl₃) δ6.96 (m, 3H), 6.81(m, 2H), 4.92 (t, J=4.9 Hz, 2H), 4.27 (m, 2H), 3.80 (m, 2H), 3.67 (m,2H), 3.52 (m, 2H), 3.18 (m, 2H), 1.49 (s, 9H); IR (diffuse reflectance)1686, 1498, 1474, 1404, 1366, 1350, 1318, 1295, 1248, 1227, 1221, 1167,1116, 788, 757 cm⁻¹; MS (EI) m/z 474 (M⁺), 418, 376, 374, 339, 334, 332,77, 57, 56, 55; Anal. Calcd for C₂₅H₂₈Cl₂N₂O₃: C, 63.16; H5.94; N, 5.89;found: C, 63.13; H, 6.00; N, 5.89.

Example 250

[1007] Preparation of7,10-Dichloro-6-(2-phenoxyethyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[1008] TFA (0.65 mL, 8.4 mmol) was added to a solution of tert-butyl7,10-dichloro-6-(2-phenoxyethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.20 g, 0.42 mmol) in CH₂Cl₂ (6 mL). After 5 h, the reaction was madebasic with 10% aqueous NaOH and extracted with CH₂Cl₂ (3×15 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄,decanted, and concentrated to give a crude solid. After thehydrochloride salt was prepared, it was further purified byrecrystallization from MeOH/EtOAc to give 51 mg (30%) of a white solid:mp 261.0-263.0° C.; ¹H NMR (300 MHz, DMSO) δ9.24 (br s, 2H), 7.26 (m,2H), 7.16 (d, J=8.3 Hz, 1H), 7.06 (d, J=8.3 Hz, 1H), 6.90 (m, 3H), 4.97(t, J=4.9 Hz, 2H), 4.26 (m, 2H), 3.53 (m, 2H); ¹³C NMR (300 MHz, DMSO)δ157.8, 141.3, 131.1, 129.4, 125.5, 123.4, 123.2, 121.3, 120.8, 114.4,114.1, 111.4, 67.7, 44.8, 43.2, 43.1, 22.2, 20.9; IR (diffusereflectance) 2965, 2952, 2826, 2794, 2741, 2676, 2650, 2443, 1496, 1467,1241, 1234, 1170, 804, 755 cm⁻¹; MS (EI) m/z 374 (M⁺), 339, 334, 332,84, 78, 77, 65, 63, 61; Anal. Calcd for C₂₀H₂₀Cl₂N₂O.HCl: C, 58.34; H,5.14; N, 6.80; found: C, 58.25; H, 5.23; N, 6.80.

[1009] Preparation 92

[1010] Preparation of tert-Butyl8,10-dichloro-6-(2-phenoxyethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylateSodium hydride (60% dispersion in mineral oil, 51 mg, 1.3 mmol) wasadded to a solution of tert-butyl8,10-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.30 g, 0.84 mmol) in DMF (5 mL). After 25 min, β-bromophenetole wasadded (0.23 mL). The reaction was quenched with saturated aqueous NH₄Clafter 18 h and extracted with EtOAc (3×15 mL). The combined organicextracts were washed with brine, dried over Na₂SO₄, decanted, andconcentrated. The crude product was purified by column chromatography(Biotage, 40S) with heptane/EtOAc (9:1) to give 0.36 g (90%) of a whitesolid: mp 131.5-133.0° C.; ¹H NMR (300 MHz, CDCl₃) δ7.04 (d, J=1.7 Hz,1H), 6.94 (t, J=7.4 Hz, 1H), 6.77 (m, 2H), 4.41 (m, 2H), 4.16 (m, 2H),3.76 (m, 2H), 3.65 (m, 2H), 3.45 (m, 2H), 3.11 (m, 2H), 1.48 (s, 9H); IR(diffuse reflectance) 2974, 2929, 1691, 1600, 1496, 1459, 1413, 1393,1365, 1348, 1303, 1243, 1170, 1114, 754 cm⁻¹; MS (EI) m/z 474 (M⁺), 420,419, 418, 417, 344, 334, 332, 57, 56; Anal. Calcd for C₂₅H₂₈Cl₂N₂O₃: C,63.16; H, 5.94; N, 5.89; found: C, 63.19; H, 5.99; N, 5.89.

Example 251

[1011] Preparation of8,10-Dichloro-6-(2-phenoxyethyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[1012] TFA (0.65 mL, 8.4 mmol) was added to a solution of tert-butyl8,10-dichloro-6-(2-phenoxyethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.20 g, 0.42 mmol) in CH₂Cl₂ (6 mL). After 5 h, thereaction was made basic with 10% aqueous NaOH and extracted with CH₂Cl₂(3×15 mL). The combined organic layers were washed with brine, driedover Na₂SO₄, decanted, and concentrated to give a crude solid. After thehydrochloride salt was prepared, it was further purified byrecrystallization from MeOH/EtOAc to give 57 mg (33%) of a white solid:mp 242.0-243.0° C.; ¹H NMR (300 MHz, DMSO) δ9.13 (br s, 2H), 7.72 (d,J=1.7 Hz, 1H), 7.26 (m, 2H), 7.13 (d, J=1.7 Hz, 1H), 6.92 (t, J=7.4 Hz,1H), 6.84 (d, J=7.9 Hz, 2H), 4.64 (m, 2H), 4.17 (m, 2H), 3.49 (m, 2H);¹³C NMR (300 MHz, DMSO) δ157.7, 139.8, 136.7, 129.4, 125.2, 124.4,121.5, 120.8, 120.0, 114.1, 110.4, 109.6, 66.5, 45.2, 43.6, 42.3, 22.3,21.0; IR (diffuse reflectance) 2843, 2718, 2688, 2666, 2633, 2440, 1601,1497, 1460, 1244, 1238, 845, 827, 754, 694 cm ¹; MS (EI) m/z 376, 374(M⁺), 339, 334, 333, 332, 78, 77, 65, 63; Anal. Calcd forC₂₀H₂₀Cl₂N₂O.HCl: C, 58.34; H, 5.14; N, 6.80; found: C, 58.10; H, 5.20;N, 6.76.

[1013] Preparation 93

[1014] Preparation of tert-Butyl8,9-dichloro-6-(2-hydroxyethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[1015] A solution of tert-butyl8,9-dichloro-6-(2-ethoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.95 g, 2.15 mmol) in dry THF (10 mL) was cooled to 0° C. Then, LiBH₄(0.14 g, 6.43 mmol) was added and the reaction was allowed to warmslowly to rt. After 17 h, the reaction was diluted with H₂O (50 mL)followed by addition of 10% aqueous NaOH (10 mL) and extraction withEtOAc (3×50 mL). The combined organic extracts were washed with brine,dried over Na₂SO₄, decanted, and concentrated. The crude product wasfirst purified by two column chromatographies (Biotage, 40M) withheptane/EtOAc (1:1) and (Biotage, 40S) with heptane/EtOAc (2:1) to give0.51 g of impure product. Finally, crystallization from Et₂O/heptanegave 0.45 g (52%) of pale yellow crystals: mp 130.5-133° C.; IR (diffusereflectance) 3469, 2976, 2937, 2869, 1676, 1477, 1449, 1415, 1366, 1342,1240, 1219, 1172, 1164, 853 cm⁻¹; MS (EI) m/z 398 (M⁺), 400, 398, 342,341, 270, 268, 86, 84, 57, 51; Anal. Calcd for C₁₉H₂₄Cl₂N₂O₃: C, 57.15;H, 6.06; N, 7.01; found: C, 57.24; H, 6.19; N, 6.95.

[1016] Preparation 94

[1017] Preparation of tert-Butyl9,10-dichloro-6-(2-hydroxyethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[1018] A solution of tert-butyl9,10-dichloro-6-(2-ethoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(1.0 g, 2.3 mmol) in dry THF (10 mL) was cooled to 0° C. Then, LiBH₄(0.15 g, 6.8 mmol) was added and the reaction was allowed to warm slowlyto rt. After 4 h, the reaction was diluted with H₂O followed by additionof 10% aqueous NaOH and extraction with EtOAc (3×50 mL). The combinedorganic extracts were washed with brine, dried over Na₂SO₄, decanted,and concentrated. The crude product was purified by columnchromatography (Biotage, 40M, SIM) with heptane/EtOAc (1:1) followed bycrystallization from EtOAc/heptane gave 0.19 g (21%) of a white solid:mp 174.5-176.0° C.; IR (diffuse reflectance) 3419, 1662, 1466, 1447,1424, 1370, 1359, 1275, 1248, 1170, 1157, 1120, 1078, 933, 799cm⁻¹; MS(EI) m/z 398 (M⁺), 400, 398, 344, 342, 341, 268, 86, 84, 57, 51; Anal.Calcd for C₁₉H₂₄Cl₂N₂O₃: C, 57.15; H, 6.06; N, 7.01; found: C, 57.13; H,6.13; N, 6.9.

[1019] Preparation 95

[1020] Preparation of tert-Butyl7,8-dichloro-6-(2-ethoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[1021] Sodium hydride (60% dispersion in mineral oil, 0.25 g, 6.3 mmol)was added to a solution of tert-butyl7,8-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(1.5 g, 4.2 mmol) in DMF (15 mL). After 20 min, ethyl bromoacetate(0.94mL, 8.4 mmol) was added. The reaction was quenched with saturatedaqueous NH₄Cl after 2.5 h and extracted with EtOAc (3×20 mL). Thecombined organic extracts were washed with brine, dried over Na₂SO₄,decanted, and concentrated. The crude product was purified by columnchromatography (Biotage, 40M) with heptane/EtOAc (3:1) followed bycrystallization from MeOH/EtOAc to give 1.5 g (81%) of a white solid: mp132.5-135.0° C.; IR (diffuse reflectance) 2974, 1747, 1683, 1465, 1450,1416, 1365, 1303, 1255, 1216, 1195, 1170, 1155, 1115, 803 cm⁻¹; MS (EI)m/z 440 (M⁺), 442, 440, 386, 385, 384, 311, 300, 298, 57, 56; Anal.Calcd for C₂₁H₂₆Cl₂N₂O₄: C, 57.15; H, 5.94; N, 6.35; found: C, 57.13; H,5.98; N, 6.36.

[1022] Preparation 96

[1023] Preparation of tert-Butyl7,8-dichloro-6-(2-hydroxyethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[1024] A solution of tert-butyl7,8-dichloro-6-(2-ethoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(3.0 g, 6.8 mmol) in dry THF (30 mL) was cooled to 0° C. Then, LiBH₄(0.74 g, 34 mmol) was added and the reaction was allowed to warm slowlyto rt. Additional LiBH₄ (0.30 g, 14 mmol) was added after 24 h. Afteranother 7 h, the reaction was diluted with H₂O (75 mL) followed byaddition of 10% aqueous NaOH and extraction with EtOAc (3×100 mL). Thecombined organic extracts were washed with brine, dried over Na₂SO₄,decanted, and concentrated. The crude product was purified by columnchromatography (Biotage, 40M, SIM) with heptane/EtOAc (1:1) followed bycrystallization from EtOAc/heptane gave 1.7 g (64%) of a white solid: mp149.0-149.5° C.; IR (diffuse reflectance) 3420, 2974, 1665, 1482, 1468,1445, 1414, 1365, 1334, 1240, 1220, 1168, 1151, 1122, 900 cm⁻¹; MS (EI)m/z 398 (M⁺), 398, 342, 298, 270, 268, 258, 256, 212, 57, 56; Anal.Calcd for C₁₉H₂₄Cl₂N₂O₃: C, 57.15; H, 6.06; N, 7.01; found: C, 57.31; H,6.10; N, 6.98

[1025] Preparation 97

[1026] Preparation of tert-Butyl7,9-dichloro-6-(2-ethoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylateSodium hydride (60% dispersion in mineral oil, 0.25 g, 6.3 mmol) wasadded to a solution of tert-butyl7,9-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(1.5 g, 4.2 mmol) in DMF (15 mL). After 20 min, ethyl bromoacetate (0.94mL, 8.4 mmol) was added. The reaction was quenched with saturatedaqueous NH₄Cl after 2 h and extracted with EtOAc (3×20 mL). The combinedorganic extracts were washed with brine, dried over Na₂SO₄, decanted,and concentrated. The crude product was purified by columnchromatography (Biotage, 40M) with heptane/EtOAc (3:1) to give 1.8 g(98%) of a white solid: mp 117.0-120.0° C.; IR (diffuse reflectance)2972, 1744, 1690, 1464, 1409, 1377, 1366, 1349, 1294, 1222, 1204, 1190,1167, 1111, 861 cm⁻¹; MS (EI) m/z 440 (M⁺), 440, 386, 385, 384, 339,311, 310, 300, 298, 57; Anal. Calcd for C₂₁H₂₆Cl₂N₂O₄: C, 57.15; H,5.94; N, 6.35; found: C, 56.97; H, 5.97; N, 6.19.

[1027] Preparation 98

[1028] Preparation of tert-Butyl7,9-dichloro-6-(2-hydroxyethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[1029] A solution of tert-butyl7,9-dichloro-6-(2-ethoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(3.00 g, 6.80 mmol) in dry THF (30 mL) was cooled to 0° C. Then, LiBH₄(0.44 g, 20.2 mmol) was added and the reaction was allowed to warmslowly to rt. After 18 h, additional LiBH₄ (0.44 g, 20.2 mmol) wasadded. After an additional 24 h, the reaction was diluted with H₂Ofollowed by addition of 10% aqueous NaOH and extraction with EtOAc. Thecombined organic extracts were washed with brine, dried over Na₂SO₄,decanted, and concentrated. The crude product was first purified bycolumn chromatography (Biotage 40M, SIM) with heptane/EtOAc (1:1) togive 2.37 g of impure product. Then, crystallization from EtOAc/heptanegave 2.21 g (82%) of ivory crystals: mp 183-184° C.; IR (diffusereflectance) 1693, 1658, 1468, 1448, 1433, 1406, 1380, 1370, 1347, 1323,1293, 1226, 1166, 1064, 771 cm⁻¹; MS (EI) m/z 398 (M⁺), 344, 342, 270,268, 258, 256, 63, 57, 56.Anal. Calcd for C₁₉H₂₄Cl₂N₂O₃: C, 57.15; H,6.06; N, 7.01; found: C, 57.20; H, 6.11; N, 6.95.

[1030] Preparation 99

[1031] Preparation of tert-Butyl7,10-dichloro-6-(2-ethoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[1032] Sodium hydride (60% dispersion in mineral oil, 0.85 g, 21 mmol)was added to a solution of tert-butyl7,10-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(5.0 g, 14 mmol) in DMF (75 mL). After 25 min, ethyl bromoacetate(3.1mL, 28 mmol) was added. The reaction was quenched with saturated aqueousNH₄Cl after 3 h and extracted with EtOAc (3×100 mL). The combinedorganic extracts were washed with brine, dried over Na₂SO₄, decanted,and concentrated. The crude product was purified by columnchromatography with heptane/EtOAc (3:1) to give 6.0 g (96%) of a whitefoam: mp 118.5-119.5° C.; IR (diffuse reflectance) 2976, 1747, 1674,1477, 1457, 1420, 1405, 1370, 1366, 1344, 1254, 1200, 1165, 1111, 930cm⁻¹; MS (EI) m/z 440 (M⁺), 386, 384, 339, 310, 305, 300, 298, 224, 57,56; Anal. Calcd for C₂₁H₂₆Cl₂N₂O₄: C, 57.15; H, 5.94; N, 6.35; found: C,57.27; H, 6.01; N, 6.22.

[1033] Preparation 100

[1034] Preparation of tert-Butyl7,10-dichloro-6-(2-hydroxyethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[1035] A solution of tert-butyl7,10-dichloro-6-(2-ethoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(3.0 g, 6.8 mmol) in dry THF (30 mL) was cooled to 0° C. Then, LiBH₄(0.74 g, 34 mmol) was added and the reaction was allowed to warm slowlyto rt. Additional LiBH₄ (0.30 g, 14 mmol) was added after 24 h. Afteranother 7 h, the reaction was diluted with H₂O (75 mL) followed byaddition of 10% aqueous NaOH and extraction with EtOAc (3×100 mL). Thecombined organic extracts were washed with brine, dried over Na₂SO₄,decanted, and concentrated. The crude product was purified by columnchromatography (Biotage, 40M, SIM) with heptane/EtOAc (1:1) followed bycrystallization from EtOAc/heptane gave 1.8 g (65%) of a white solid: mp156.0-158.5° C.; IR (diffuse reflectance) 1686, 1652, 1476, 1433, 1414,1400, 1364, 1353, 1319, 1302, 1229, 1178, 1156, 1063, 972 cm⁻¹; MS (EI)m/z 398 (M⁺), 398, 342, 270, 268, 263, 258, 256, 212, 57, 56; Anal.Calcd for C₁₉H₂₄Cl₂N₂O₃: C, 57.15; H, 6.06; N, 7.01; found: C, 57.23; H,6.10; N, 7.00.

[1036] Preparation 101

[1037] Preparation of tert-Butyl8,10-dichloro-6-(2-ethoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[1038] Sodium hydride (60% dispersion in mineral oil, 0.25 g, 6.3 mmol)was added to a solution of tert-butyl8,10-dichloro-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(1.5 g, 4.2 mmol) in DMF (15 mL). After 20 min, ethyl bromoacetate(0.94mL, 8.4 mmol) was added. The reaction was quenched with saturatedaqueous NH₄Cl after 1.5 h and extracted with EtOAc (3×20 mL). Thecombined organic extracts were washed with brine, dried over Na₂SO₄,decanted, and concentrated. The crude product was purified by columnchromatography (Biotage, 40M) with heptane/EtOAc (3:1) followed bycrystallization from MeOH/EtOAc to give 1.4 g (78%) of a white solid: mp144.5-147.0° C.; IR (diffuse reflectance) 2982, 2972, 1748, 1690, 1456,1411, 1373, 1366, 1352, 1252, 1222, 1202, 1159, 1115, 824 cm⁻¹; MS (EI)m/z 440 (M⁺), 442, 440, 386, 384, 310, 300, 298, 86, 84, 57; Anal. Calcdfor C₂₁H₂₆Cl₂N₂O₄: C, 57.15; H, 5.94; N, 6.35; found: C, 57.15; H, 6.04;N, 6.37

[1039] Preparation 102

[1040] Preparation of tert-Butyl8,10-dichloro-6-(2-hydroxyethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[1041] A solution of tert-butyl8,10-dichloro-6-(2-ethoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(3.0 g, 6.8 mmol) in dry THF (30 mL) was cooled to 0° C. Then, LiBH₄(0.74 g, 34 mmol) was added and the reaction was allowed to warm slowlyto rt. After 24 h, the reaction was diluted with H₂O (75 mL) followed byaddition of 10% aqueous NaOH (30 mL) and extraction with EtOAc (3×100mL). The combined organic extracts were washed with brine, dried overNa₂SO₄, decanted, and concentrated. The crude product was purified bycolumn chromatography (Biotage, 40M, SIM) with heptane/EtOAc (1:1)followed by crystallization from EtOAc/heptane gave 1.6 g (58%) of awhite solid: mp 166.5-167.0° C.; IR (diffuse reflectance) 3462, 1665,1458, 1426, 1367, 1362, 1342, 1264, 1249, 1165, 1115, 1081, 931, 828,820cm⁻¹; MS (El ) m/z 398 (M⁺), 398, 342, 341, 298, 270, 268, 258, 256,57, 56; Anal. Calcd for C₁₉H₂₄Cl₂N₂O₃: C, 57.15; H, 6.06; N, 7.01;found: C, 57.08; H, 6.08; N, 6.97.

Examples 252-307

[1042] Using the following general procedure the compounds of Examples251-306 were prepared.

[1043] The appropriate aryl alcohol (0.50 mmol) was added to a 20 mLscintillation vial followed by the addition of a stock solution of theappropriate dichloroazepinoindole alcohol (0. 10 g, 0.25 mmol) and PPh₃(99 mg, 0.38 mmol) in THF (5 mL). Next, a stock solution of DBAD (87 mg,0.38 mmol) in THF (3 mL) was added to each vial. The vials were capped,placed in a J-KEM® heater block attached to a Lab-Line® orbit shaker andshaken (250 RPM) at 40° C. overnight. A subset of the reactions wasmonitored by LC/MS. After all the starting alcohol was consumed in thesereactions, MeOH (3 mL) and Dowex® 50WX2-400 ion-exchange resin (0.75 g)was added to each vial. The reactions were then shaken (300 RPM) at 40°C. until the product was on the resin, based on LC/MS monitoring. Thevials were cooled to rt and transferred with 2×5 mL of CH₂Cl₂/MeOH (3:1)to disposable fritted syringe barrels on a syringe washing station. Theresin was then rinsed with 3×10 mL of pyridine/MeOH (3:7), 1×10 mL ofCH₂Cl₂, and 3×10 mL of MeOH. The syringe barrels were then transferredto a vacuum manifold and the product was eluted off the resin with atotal of 10×5 mL of MeOH/NH₄OH (3:1) into two 40 mL scintillation vialsfor each compound. The vials were blown down under nitrogen and followedby further drying in the vacuum oven overnight at 47° C. to giveproduct. The products were evaluated by HPLC and MS or LC/MS.

Example 252

[1044]8,9-Dichloro-6-{2-[(5,7-dibromo-8-quinolinyl)oxy]ethyl}-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole;

[1045] MS (ESI+) 583.3 m/z (MH⁺).

Example 253

[1046]9,10-Dichloro-6-{2-[(5,7-dibromo-8-quinolinyl)oxy]ethyl}-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole;

[1047] MS (ESI+) 583.8 m/z (MH⁺).

Example 254

[1048]7,8-Dichloro-6-{2-[(5,7-dibromo-8-quinolinyl)oxy]ethyl}-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1049] MS (ESI+) 583.8 m/z (MH⁺).

Example 255

[1050]7,9-Dichloro-6-{2-[(5,7-dibromo-8-quinolinyl)oxy]ethyl}-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1051] MS (ESI+) 583.8 m/z (MH⁺).

Example 256

[1052]7,10-Dichloro-6-{2-[(5,7-dibromo-8-quinolinyl)oxy]ethyl}-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1053] MS (ESI+) 583.8 mz (MH⁺).

Example 257

[1054]8,10-Dichloro-6-{2-[(5,7-dibromo-8-quinolinyl)oxy]ethyl}-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1055] MS (ESI+) 583.8 m/z (MH⁺).

Example 258

[1056]8,9-Dichloro-6-{2-(8-quinolinyloxy)ethyl}-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1057] MS (ESI+) 425.8 m/z (MH⁺).

Example 259

[1058]9,10-Dichloro-6-[2-(8-quinolinyloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1059] MS (ESI+) 426.0 m/z (MH⁺).

Example 260

[1060]7,8-Dichloro-6-[2-(8-quinolinyloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1061] MS (ESI+) 426.0 m/z (MH⁺).

Example 261

[1062]7,9-Dichloro-6-[2-(8-quinolinyloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1063] MS (ESI+) 426.1 m/z (MH⁺).

Example 262

[1064]7,10-Dichloro-6-[2-(8-quinolinyloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1065] MS (ESI+) 425.9 m/z (MH⁺).

Example 263

[1066]8,10-Dichloro-6-[2-(8-quinolinyloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1067] MS (ESI+) 426.0 m/z (MH⁺).

Example 264

[1068]8,9-Dichloro-6-[2-(5-isoquinolinyloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1069] MS (ESI+) 425.8 m/z (MH⁺).

Example 265

[1070]7,8-Dichloro-6-[2-(5-isoquinolinyloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1071] MS (ESI+) 425.9 m/z (MH⁺).

Example 266

[1072]7,9-Dichloro-6-[2-(5-isoquinolinyloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1073] MS (ESI+) 426.1 m/z (MH⁺).

Example 267

[1074]8,10-Dichloro-6-[2-(5-isoquinolinyloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1075] MS (ESI+) 426.1 m/z (MH⁺).

Example 268

[1076]8,9-Dichloro-6-[2-(5-quinolinyloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1077] MS (ESI+) 425.8 m/z (MH⁺).

Example 269

[1078]9,10-Dichloro-6-[2-(5-quinolinyloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1079] MS (ESI+) 426.0 m/z (MH⁺).

Example 270

[1080]7,8-Dichloro-6-[2-(5-quinolinyloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1081] MS (ESI+) 426.1 m/z (MH⁺).

Example 271

[1082]7,9-Dichloro-6-[2-(5-quinolinyloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1083] MS (ESI+) 426.1 m/z (MH⁺).

Example 272

[1084]7,10-Dichloro-6-[2-(5-quinolinyloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1085] MS (ESI+) 425.9 m/z (MH⁺).

Example 2738,10-Dichloro-6-[2-(5-quinolinyloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1086]

[1087] MS (ESI+) 426.0 m/z (MH⁺).

Example 274

[1088]8,9-Dichloro-6-[2-(5,6,7,8-tetrahydro-1-naphthalenyloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1089] MS (ESI+) 428.8 m/z (MH⁺).

Example 275

[1090]9,10-Dichloro-6-[2-(5,6,7,8-tetrahydro-1-naphthalenyloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1091] MS (ESI+) 429.1 m/z (MH⁺).

Example 276

[1092]7,8-Dichloro-6-[2-(5,6,7,8-tetrahydro-1-naphthalenyloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1093] MS (ESI+) 429.1 m/z (MH⁺).

Example 277

[1094]7,9-Dichloro-6-[2-(5,6,7,8-tetrahydro-1-naphthalenyloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1095] MS (ESI+) 429.1 m/z (MH⁺).

Example 278

[1096]7,10-Dichloro-6-[2-(5,6,7,8-tetrahydro-1-naphthalenyloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1097] MS (ESI+) 429.0 m/z (MH⁺).

Example 279

[1098]8,10-Dichloro-6-[2-(5,6,7,8-tetrahydro-1-naphthalenyloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1099] MS (ESI+) 429.1 m/z (MH⁺).

Example 280

[1100]6-[2-(1,3-Benzodioxol-5-yloxy)ethyl]-8,9-dichloro-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1101] MS (ESI+) 418.7 m/z (MH⁺).

Example 281

[1102]6-[2-(1,3-Benzodioxol-5-yloxy)ethyl]-9,10-dichloro-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1103] MS (ESI+) 419.0 m/z (MH⁺).

Example 282

[1104]6-[2-(1,3-Benzodioxol-5-yloxy)ethyl]-7,8-dichloro-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1105] MS (ESI+) 419.0 m/z (MH⁺).

Example 283

[1106]6-[2-(1,3-Benzodioxol-5-yloxy)ethyl]-7,9-dichloro-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1107] MS (EST+) 419.1 m/z (MH⁺).

Example 284

[1108]6-[2-(1,3-Benzodioxol-5-yloxy)ethyl]-7,10-dichloro-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1109] MS (ESI+) 419.0 m/z (MH⁺).

Example 285

[1110]6-[2-(1,3-Benzodioxol-5-yloxy)ethyl]-8,10-dichloro-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1111] MS (ESI+) 419.0 m/z (MH⁺).

Example 286

[1112]8,9-Dichloro-6-[2-(1H-indol-4-yloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1113] MS (ESI+) 414.1 m/z (MH⁺).

Example 287

[1114]9,10-Dichloro-6-[2-(1H-indol-4-yloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1115] MS (ESI+) 414.1 n/z (MH⁺).

Example 288

[1116]7,8-Dichloro-6-[2-(1H-indol-4-yloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1117] MS (ESI+) 414.1 m/z (MH⁺).

Example 289

[1118]8,10-Dichloro-6-[2-(1H-indol-4-yloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1119] MS (ESI+) 414.1 m/z (MH⁺).

Example 290

[1120]8,9-Dichloro-6-[2-(5,6,7,8-tetrahydro-2-naphthalenyloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1121] MS (ESI+) 429.3 m/z (MH⁺).

Example 291

[1122]9,10-Dichloro-6-[2-(5,6,7,8-tetrahydro-2-naphthalenyloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1123] MS (ESI+) 429.1 m/z (MH⁺).

Example 292

[1124]7,8-Dichloro-6-[2-(5,6,7,8-tetrahydro-2-naphthalenyloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1125] MS (ESI+) 429.1 m/z (MH⁺).

Example 293

[1126]7,9-Dichloro-6-[2-(5,6,7,8-tetrahydro-2-naphthalenyloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1127] MS (ESI+) 429.1 m/z (MH⁺).

Example 294

[1128]7,10-Dichloro-6-[2-(5,6,7,8-tetrahydro-2-naphthalenyloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1129] MS (ESI+) 429.0 m/z (MH⁺).

Example 295

[1130]8,10-Dichloro-6-[2-(5,6,7,8-tetrahydro-2-naphthalenyloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1131] MS (ESI+) 429.1 m/z (MH⁺).

Example 296

[1132]8,9-Dichloro-6-[2-(7-quinolinyloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1133] MS (ESI+) 426.2 m/z (MH⁺).

Example 297

[1134]9,10-Dichloro-6-[2-(7-quinolinyloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1135] MS (ESI+) 426.1 m/z (MH⁺).

Example 298

[1136]7,8-Dichloro-6-[2-(7-quinolinyloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1137] MS (ESI+) 426.1 m/z (MH⁺).

Example 299

[1138]7,9-Dichloro-6-[2-(7-quinolinyloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1139] MS (ESI+) 426.1 m/z (MH⁺).

Example 300

[1140]7,10-Dichloro-6-[2-(7-quinolinyloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1141] MS (ESI+) 426.0 m/z (MH⁺).

Example 301

[1142]8,10-Dichloro-6-[2-(7-quinolinyloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1143] MS (ESI+) 426.0 m/z (MH⁺).

Example 302

[1144]8,9-Dichloro-6-{2-[(5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-1-yl)oxy]ethyl}1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1145] MS (ESI+) 457.2 m/z (MH⁺).

Example 303

[1146]9,10-Dichloro-6-{2-[(5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-1-yl)oxy]ethyl}1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1147] MS (ESI+) 457.2 m/z (MH⁺).

Example 304

[1148]7,8-Dichloro-6-{2-[(5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-1-yl)oxy]ethyl}-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1149] MS (ESI+) 457.2 m/z (MH⁺).

Example 305

[1150]7,9-Dichloro-6-{2-[(5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-1-yl)oxy]ethyl}-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1151] MS (ESI+) 457.2 m/z (MH⁺).

Example 306

[1152]7,10-Dichloro-6-{2-[(5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-1-yl)oxy]ethyl}1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1153] MS (ESI+) 457.2 m/z (MH⁺).

Example 307

[1154]8,10-Dichloro-6-{2-[(5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-1-yl)oxy]ethyl}-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole:

[1155] MS (ESI+) 457.2 m/z (MH⁺).

[1156] Preparation 103

[1157] Preparation of3-tert-butyloxycarbonyl-9-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[1158] In a 500 mL round-bottomed flask a mixture of3-benzoyl-9-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (12.9 g,35.0 mmol), KOH (9.8 g, 175 mmol), and ethylene glycol (250 mL) washeated at 140° C. overnight. The mixture was cooled to 0° C. and dioxane(150 mL) and Boc₂O (8.4 g, 38.5 mmol) were added and stirred for 1 h.The bath was removed and the mixture was stirred at room temperature for18 h, and then heated at 100° C. for 6 h. Heat was removed and themixture was allowed to stir at room temperature for 72 h. Dioxane wasremoved under reduced pressure and the resulting mixture was partitionedbetween CHCl₃ and water. The aqueous layer was extracted a second timewith CHCl₃ and the combined organic layers were washed with water andconcentrated to give 12.5 g of an oily brown foam. A precipitate formedupon dissolution in CHCl₃ and was filtered to give 3.21 g (25%) of titlecompound as an off-white solid. 3.65 g of additional material obtainedfrom a second precipitation contained 20% impurity. Columnchromatography of the second lot of mother liquors (elution with 20-50%EtOAc/heptane) gave an additional 1.3 g (10%) of the title compound as ayellow solid. The mixture was resubmitted to the reaction conditions andthe resulting 3.27 g (25%) of the title compound obtained as anoff-white solid was submitted for analysis: mp 200-203° C. (dec); ¹H NMR(400 MHz, CDCl₃) δ7.96 (br s, 1 H), 7.56 (s, 1 H), 7.19 (dd, J=1.7, 8.5Hz, 1 H), 7.12 (d, J=8.5 Hz, 1 H), 3.73-3.62 (m, 4 H), 3.03-2.95 (m, 2H), 2.95-2.86 (m, 2 H), 1.49 (s, 9 H); IR (drift) 3294, 1667, 1478,1423, 1366, 1326, 1286, 1266, 1249, 1238, 1169, 1118, 927, 857, 790cm⁻¹.

[1159] Preparation 104

[1160] Preparation of3-(tert-Butyloxycarbonyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole.

[1161] Following the general procedure of

[1162] Preparation 9, but starting with3-(tert-butyloxycarbonyl)-9-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(6.50 g, 17.8 mmol), the title compound was obtained as a yellow solid(2.70 g, 37%): mp 234-237° C.; ¹H NMR (300 MHz, CDCl₃) δ7.99 (s, 1 H),7.82 (br s, 1 H), 7.57 (d, J=8 Hz, 1 H), 7.26-7.24 (m, 1 H), 3.75-3.60(m, 4 H), 3.07-2.93 (m, 4 H), 1.48 (s, 9 H), 1.36 (s, 12 H). MS (FAB)m/z 413 (M+H³⁰), 412, 411, 358, 357, 356, 355, 354, 282, 57; HRMS (EI)calcd for C₂₃H₃₃BN₂O₄ 412.2533, found 412.2541.

[1163] Preparation 105

[1164] Preparation of tert-Butyl9-(2,6-difluorophenyl)-1,4,5,6-tetrahydroazepino-[4,5-b]indole-3(2H)-carboxylate.

[1165] A solution of 1-bromo-2,6-difluorobenzene (0.28 g, 1.5 mmol) indioxane (12 mL) was added to a flask charged with3-(tert-butyloxycarbonyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(0.50 g, 1.2 mmol), Pd₂(dba)₃ (0.11 g, 0.12 mmol) and potassiumphosphate(0.59 g, 2.8 mmol). Next, trimethylphosphite (0.045 mL, 0.38mmol) was added and the mixture was heated to 95° C. After 28.5 h, thereaction was cooled to rt, diluted with H₂O, and extracted with EtOAc(3×50 mL). The combined organic extracts were washed with brine, driedover Na₂SO₄, decanted, and concentrated. The crude product was purifiedby column chromatography (Biotage, 40M, SIM) with heptane/EtOAc (4:1) togive 0.38 g (80%) of a pale yellow solid: mp 225.5-226° C.; % water(KF): 0.10; melt solvate: 1.46% CH₂Cl₂; 0.19% EtOAc; Anal. Calcd forC₂₃H₂₄F₂N₂O₂.0.10% H₂O.1.46% CH₂Cl₂.0.19% EtOAc: C, 68.34; H, 6.19; N,6.91; found: C, 68.34; H, 6.19; N, 6.81.

Example 308

[1166] 9-(2,6-Difluorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[1167] TFA (1.9 mL, 25 mmol) was added to a mixture of tert-butyl9-(2,6-difluorophenyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.48 g, 1.2 mmol) in CH₂Cl₂ (25 mL). After 1 h, the reaction wasquenched with 10% aqueous NaOH and diluted with H₂O. The layers wereseparated and the aqueous layer was extracted with CH₂Cl₂ (3×25 mL). Thecombined organic extracts were washed with brine, dried over Na₂SO₄,decanted, and concentrated. The crude product was purified by columnchromatography (Biotage, 40S, SIM) with CH₂Cl₂/MeOH/NH₄OH (976:21:3) togive 0.30 g (85%) of the free base. The HCl salt was prepared from 100mg of free base as a gray-brown solid (73 mg): mp 285.5-287.5° C.; IR(diffuse reflectance) 3226, 2949, 2827, 2800, 2753, 1589, 1468, 1449,1425, 1268, 1228, 995, 802, 780, 731 cm⁻¹; MS (EI) m/z 298 (M⁺), 269,268, 257, 256, 255, 78, 64, 63, 62; Anal. Calcd for C₁₈H₁₆F₂N₂.HCl: C,64.57; H, 5.12; N, 8.37; found: C, 64.51; H, 5.22; N, 8.29.

[1168] Preparation 106

[1169] Preparation of3-Benzoyl-9-(4-methoxy-2-methylphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole.

[1170] A solution of3-benzoyl-9-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1.50 g,4.06 mmol) in DME (50 mL) was degassed via sonication and vacuum/N₂purge. Then, (PhP₃)₄Pd (0.235 g, 0.203 mmol) was added and the mixturewas stirred for 20 min prior to the addition of a solution oftris(4-methoxy-2-methylphenyl)boroxin (0.900 g, 2.03 mmol) in DME (10mL) and MeOH (2.5 mL). Next, 2M Na₂CO₃ (12 mL) was added and thereaction was heated to reflux. After 7 h, additional (PhP₃)₄Pd (0.235 g,0.203 mmol) was added. The reaction was cooled to rt after an additional15 h. The reaction was partitioned between H₂O and EtOAc and the layerswere separated. The aqueous layer was extracted with additional EtOAc(2×100 mL). The combined organic extracts were washed with brine, driedover Na₂SO₄, decanted, and concentrated. The crude product was purifiedby column chromatography (Biotage, 40M) with heptane/EtOAc (gradient,2:1 to 1:1) to give 0.61 (37%) of the title compound. An analyticalsample was prepared, via crystallization from heptane/EtOAc, as anoff-white solid: mp 268.5-271.5° C.; IR (diffuse reflectance) 3297,3250, 3243, 3202, 1608, 1500, 1467, 1430, 1300, 1289, 1276, 1233, 786,740, 706 cm⁻¹; MS (EI) m/z 410 (M⁺), 290, 289, 288, 276, 105, 86, 77,51, 50; HRMS (FAB) calcd for C₂₇H₂₆N₂O₂+H 411.2072, found 411.2073; %water (KF): 0.23; melt solvate: 1.91% EtOAc, 0.15% heptane; Anal. Calcdfor C₂₇H₂₆N₂O₂.0.23% H₂O.1.91% EtOAc-0.15% heptane: C, 78.36; H, 6.46;N, 6.67; found: C, 78.16; H, 6.47; N, 6.91.

Example 309

[1171]9-(4-Methoxy-2-methylphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[1172] A mixture of3-benzoyl-9-(4-methoxy-2-methylphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(0.40 g, 0.97 mmol), potassium hydroxide (1.0 g, 18 mmol) and ethyleneglycol (10 mL) was heated to 170° C. After 3 h, the reaction was cooledto rt, diluted with H₂O, and extracted with CH₂Cl₂. The combined organicextracts were washed with brine, dried over K₂CO₃, decanted, andconcentrated to give 0.26 g (87%) of crude product. The HCl salt wasprepared from 100 mg of free base as a light brown solid (39 mg): mp276.5-277° C.; IR (diffuse reflectance) 3226, 3004, 2986, 2958, 2938,2832, 2798, 2752, 1609, 1468, 1449, 1420, 1292, 1235, 800 cm⁻¹; MS (EI)m/z 306 (M⁺), 277, 264, 86, 84, 78, 63, 62, 61, 51 HRMS (FAB) calcd forC₂₀H₂₂N₂O+H 307.1810, found 307.1806.

[1173] Preparation 107

[1174] Preparation of3-Benzoyl-9-(2,4-dichlorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole.

[1175] A solution of3-benzoyl-9-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (2.00 g,5.42 mmol) in DME (50 mL) was degassed via vacuum/N₂ purge. Then,(PhP₃)₄Pd (0.63 g, 0.54 mmol) was added and the mixture was stirred for20 min prior to the addition of a degassed solution of2,4-dichlorophenylboronic acid (1.55 g, 8.12 mmol) in DME (10 mL) andMeOH (0.5 mL). Next, 2M Na₂CO₃ (16 mL) was added and the reaction washeated to reflux. After 2 h, the reaction was cooled to rt andpartitioned between H₂O and EtOAc. The layers were separated and theaqueous layer was extracted with additional EtOAc (2×75 mL). Thecombined organic extracts were washed with brine, dried over Na₂SO₄,decanted, and concentrated. The crude product was purified by columnchromatography with heptane/EtOAc (gradient, 1:1 to 1:2) to give 2.15 gof impure product. Triturating with ether and extended drying undervacuum gave 1.42 g (60%) of gray-brown solid: mp 235.5-237° C.; IR(diffuse reflectance) 3294, 1601, 1468, 1434, 1374, 1330, 1295, 1246,933, 873, 821, 796, 785, 743, 708 cm⁻¹; MS (EI) m/z 434 (M⁺), 315, 313,300, 105, 78, 77, 64, 63, 51; HRMS (FAB) calcd for C₂₅H₂₀CL₂N₂O+H435.1031, found 435.1017; % Water (KF): 0.10; melt solvate: 0.84% EtOAc.

Example 310

[1176] 9-(2,4-Dichlorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[1177] A mixture of3-benzoyl-9-(2,4-dichlorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(1.00 g, 2.30 mmol), potassium hydroxide (2.00 g, 35.6 mmol) andethylene glycol (20 mL) was heated to 170° C. After 3 h, the reactionwas cooled to rt, diluted with H₂O, and extracted with CH₂Cl₂. Thecombined organic extracts were washed with brine, dried over K₂CO₃,decanted, and concentrated to give 0.74 g (97%) of crude product. TheHCl salt was prepared from 100 mg of free base as a beige solid (57 mg):mp 273-274.5° C.; IR (diffuse reflectance) 3230, 2952, 2827, 2799, 2753,2679, 2576, 1594, 1469, 1454, 1421, 1330, 827, 813, 799 cm⁻¹; MS (EI)m/z 332, 330 (M⁺), 303, 301, 300, 292, 290, 289, 288, 287; Anal. Calcdfor C₁₈H₁₆Cl₂N₂.HCl: C, 58.80; H, 4.66; N, 7.62; found: C, 58.76; H,4.76; N, 7.53.

Example 311

[1178]N-(3-chloro-2-methylphenyl)-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamidehydrochloride

[1179] Prepared according to the procedure used to prepareN-(2,3-dimethylphenyl)-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamidehydrochloride. 1H NMR (CD₃OD) δ7.52, 7.42, 7.29, 7.23-7.11, 5.13, 3.52,3.47, 3.32, 3.23, 2.25. MS (ESI+) for C₂₁H₂₀ClN₃O m/z 368.0 (M+H)⁺.

Example 312

[1180]N-[2-methyl-3-(trifluoromethyl)phenyl]-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamidehydrochloride

[1181] Prepared according to the procedure used to prepareN-(2,3-dimethylphenyl)-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamidehydrochloride. ¹H NMR (CD₃OD) δ7.56, 7.44, 7.35, 7.22, 7.12, 5.17, 3.53,3.47, 3.33, 3.23, 2.32. MS (ESI+) for C₂₂H₂₂F₃N₃O m/z 402.0 (M+H)⁺.

Example 313

[1182]2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(5,6,7,8-tetrahydronaphthalen-1-yl)acetamidehydrochloride

[1183] Prepared according to the procedure used to prepareN-(2,3-dimethylphenyl)-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamidehydrochloride. ¹H NMR (CD₃OD) δ7.52, 7.43, 7.21, 7.14, 7.06, 6.97, 5.10,3.51, 3.45, 3.32, 3.22, 2.76, 2.55, 1.76. MS (ESI+) for C₂₄H₂₇N₃O m/z374.1 (M+H)⁺.

Example 314

[1184]N-(4-methyl-1,3-thiazol-2-yl)-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamidehydrochloride

[1185] Prepared according to the procedure used to prepareN-(2,3-dimethylphenyl)-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamidehydrochloride. 1H NMR (CDCl₃) δ7.53, 7.35, 7.18, 7.11, 6.94, 5.83, 3.51,3.32, 3.26, 2.41. MS (ESI+) for C₁₈H₂₀N₄OS m/z 341.1 (M+H)⁺.

Example 315

[1186]N-(1,3-dihydro-2-benzofuran-4-yl)-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamidehydrochloride

[1187] Prepared according to the procedure used to prepareN-(2,3-dimethylphenyl)-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamidehydrochloride. ¹H NMR (CD₃OD) δ7.51, 7.37, 7.27, 7.20, 7.11, 5.10, 5.06,4.98, 3.51, 3.46, 3.29, 3.22. MS (ESI+) for C₂₂H₂₃NO₂ m/z 362.2 (M+H)⁺.

Example 316

[1188]2-(7-bromo-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(4-methyl-1,3-thiazol-2-yl)acetamidehydrochloride

[1189] tert-Butyl7-bromo-6-{2-[(4-methyl-1,3-thiazol-2-yl)amino]-2-oxoethyl}-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.280 g,0.52 mmol) was dissolved in EtOAc (15 mL). 4N HCl in dioxane (5 mL) wasadded and the reaction mixture was stirred at rt under N₂. After 1 h, awhite solid precipitated from the solution. The precipitate wascollected by filtration. Pure2-(7-bromo-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(4-methyl-1,3-thiazol-2-yl)acetamidehydrochloride was obtained after recrystallization from 3:1 CH₃OH:Et₂O(20 mL), as a white solid (0.220 g) in 94% yield. ¹H NMR (400 MHz,CD₃OD) δ2.4, 3.22-3.28, 3.49-3.59, 5.7-5.78, 6.88, 7.02, 7.35, 7.54; MS(ESI+) for C₁₈H₁₉BrN₄OS m/z 420.8 (M+H)⁺.

Example 317

[1190]2-(8-bromo-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(4-methyl-1,3-thiazol-2-yl)acetamidehydrochloride

[1191] Prepared according to the procedure used to prepare2-(7-bromo-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(4-methyl-1,3-thiazol-2-yl)acetamidehydrochloride in 53% yield. 1H NMR (400 MHz, CD₃OD) δ2.38, 3.21-3.29,3.46-3.56, 5.24, 6.83, 7.25, 7.46, 7.58; MS (ESI+) for C₁₈H₁₉BrN₄OS m/z420.8 (M+H)⁺.

Example 318

[1192] 2-(9-bromo-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(4-methyl-1,3-thiazol-2-yl)acetamide hydrochloride

[1193] Prepared according to the procedure used to prepareN-(2,3-dimethylphenyl)-2-(2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetamidehydrochloride in 14% yield. ¹H NMR (400 MHz, CD₃OD) δ2.33, 3.18-3.29,3.46-3.55, 5.19, 6.69, 7.28, 7.69; MS (ESI+) for C₁₈H₁₉BrN₄OS m/z 420.9(M+H)⁺.

Example 319

[1194]2-(10-bromo-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(4-methyl-1,3-thiazol-2-yl)acetamide

[1195] tert-Butyl 10-bromo-6-{2-[(4-methyl-1,3-thiazol-2-yl)amino]-2-oxoethyl}-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.13 g,0.24 mmol) was dissolved in CH₂Cl₂ (5 mL). CF₃CO₂H (0.5 mL, 0.74 g, 6.5mmol) was added. The reaction mixture was stirred at rt under N₂ for 46h. The reaction mixture was partitioned between 1N NaOH (60 mL) andEtOAc (350 mL). The aqueous layer was back extracted with EtOAc (100mL). The combined organic layers were washed with brine (25 mL), driedover MgSO₄, filtered and concentrated under reduced pressure. The crudeproduct was flash chromatographed (10% CH₃OH/CH₂Cl₂ containing 0.05% 7NNH₃/CH₃OH) and2-(10-bromo-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)-N-(4-methyl-1,3-thiazol-2-yl)acetamidewas obtained in 28% yield. ¹H NMR (400 MHz, CD₃OD) δ2.33, 3.02-3.09,3.14-3.21, 3.55-3.63, 5.16, 6.67, 6.97, 7.21, 7.30; MS (ESI+) forC₁₈H₁₉BrN₄OS m/z 420.8 (M+H)⁺.

Example 320

[1196]6-[2-(5,6,7,8-tetrahydronaphthalen-1-yloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[1197] tert-Butyl6-(2-hydroxyethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.100 g, 0.302 mmol) was dissolved in THF (6 mL).5,6,7,8-Tetrahydronaphthalen-1-ol (0.067 g, 0.454 mmol) was added, andafter 25 min di-tert-butyl azodicarboxylate (0.105 g, 0.454 mmol) wasadded. The reaction mixture was stirred at 40° C. for 5 h. The solventwas removed in vacuo. The crude product was flash chromatographed (9:1hexane:EtOAc) and tert-butyl6-[2-(5,6,7,8-tetrahydronaphthalen-1-yloxy)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylatewas obtained in 22% yield. tert-Butyl6-[2-(5,6,7,8-tetrahydronaphthalen-1-yloxy)ethyl]-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.028 g, 0.061 mmol) was dissolved in EtOAc (5 mL). 4N HCl in dioxane(2 mL) was added. The reaction mixture was stirred at rt under N₂ for 20h. The solvent was removed in vacuo. The crude product was dissolved inEtOAc (2 mL) and Et₂O (3 mL) was added dropwise. The precipitate wascollected by filtration, wash with Et₂O and dried in vacuo at reducedpressure to yield6-[2-(5,6,7,8-tetrahydronaphthalen-1-yloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride in 73% yield. ¹H NMR (400 MHz, CD₃OD) δ1.66-1.72,2.35-2.39, 2.65-2.72, 3.20-3.23, 3.36-3.50, 4.23-4.28,4.61-4.64, 6.51,6.63, 6.93, 7.10, 7.18, 7.44, 7.50; MS (ESI+) for C₂₄H₂₈N₂O m/z 361.1(M+H)⁺.

Example 321

[1198]6-{2-[(5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-1-yl)oxy]ethyl}-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[1199] Prepared according to the procedure used to prepare6-[2-(5,6,7,8-tetrahydronaphthalen-1-yloxy)ethyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole hydrochloride in 69% yield. ¹H NMR(400 MHz, CD₃OD) δ1.20-1.26, 1.53-1.61, 1.63-1.73, 2.34-2.40, 3.21-3.26,3.37-3.53, 4.22-4.28, 4.59-4.66, 6.53, 6.93, 6.99, 7.10, 7.18, 7.42,7.50; MS (ESI+) for C₂₆H₃₂N₂O m/z 389.1 (M+H)⁺.

[1200] Preparation 108

[1201] Preparation of3-benzoyl-10-(2-chlorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[1202] Prepared according to the procedure used to prepare3-benzoyl-10-[2-(trifluoromethoxy)phenyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole.¹H NMR (400 MHz, CD₃OD) δ2.15, 2.27, 2.39, 2.53, 2.92, 3.19, 3.42, 3.65,3.71, 3.95, 6.72, 7.08, 7.26-7.35, 7.36-7.55; MS (ESI+) for C₂₅H₂₁ClN₂Om/z 401.0 (M+H)⁺.

Example 322

[1203]10-(2-chlorophenyl)-3-methyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[1204] Obtained as a minor product, in 21% yield, from the deprotectionreaction of3-benzoyl-10-(2-chlorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolewith KOH in ethylene glycol at 170° C. for 26 h. ¹H NMR (400 MHz, CD₃OD)δ2.26, 2.35-2.46, 2.53-2.60, 2.77-2.84, 2.97-3.02, 6.72, 7.06, 7.29,7.32-7.40, 7.48; MS (ESI+) for C₁₉H₁₉ClN₂m/z 311.1 (M+H)⁺.

Example 323

[1205] 10-(2-chlorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[1206] Prepared according to the procedure used to prepare10-[2-(trifluoromethoxy)phenyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolein 96% yield. ¹H NMR (400 MHz, CD₃OD) δ2.31, 2.45, 2.86-2.93, 3.04-3.10,3.12-3.18, 6.73, 7.08, 7.31, 7.33-7.40, 7.48; MS (ESI+) for C₁₈H₆ClN₂m/z 297.1 (M+H)⁺.

[1207] Preparation 109

[1208] Preparation of tert-butyl10-(2-methylphenyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[1209] tert-Butyl10-bromo-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(1.17g, 3.2 mmol), Pd(PPh₃)₄ (0.39 g, 0.34 mmol), and dimethoxyethane(25 mL) were stirred at room temperature for 10 minutes then treatedwith 2-methylboronic acid (0.52 g, 3.8 mmol) and a 2 M solution ofNa₂CO₃ (12 mL). The reaction was heated to reflux for 15.25 hours thencooled to room temperature and partitioned between ethyl acetate andwater. The aqueous layer was extracted with ethyl acetate (2×) and theorganic layers were combined, washed with brine, dried over MgSO₄ andconcentrated in vacuo to give a brown oil which was passed through acolumn of silica gel with 1:5 ethyl acetate/hexane to give 0.53 g (44%)of a brown oil as the title compound.

Example 324

[1210] 10-(2-methylphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[1211] The tert-butyl10-(2-methylphenyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.53 g, 1.40 mmol) from above was treated with a solution of 4 N HCl indioxane (10 mL) and stirred at room temperature for 3.7 hours. After thereaction mixture was concentrated in vacuo CH₂Cl₂ was added and thesolution was concentrated in vacuo to give a green solid (475 mg) whichwas recrystallized from CH₃OH/ethyl acetate to give 0.362 g (82%) of alight brown solid as the title compound: mp 278.5-281° C. ¹H NMR (400MHz, DMSO-d₆) δ11.20 (s, 1 H), 9.40 (br s, 1 H), 7.32-7.22 (m, 4 H),7.15 (d, J=7.2 Hz, 1H), 7.09-7.05 (m, 1 H), 6.68 (d, J=7.1 Hz, 1 H),3.26 (m, 2 H), 3.17-3.16 (m, 2 H). 2.98 (m, 2 H), 2.37-2.27 (m, 2 H),1.98 (s, 3 H); ¹³C NMR (100 MHz, DMSO-d₆) δ140.9, 135.8, 135.5, 134.5,132.7, 129.4, 129.2, 127.2, 125.3, 125.0, 120.2, 119.7, 110.0, 109.7,45.9, 44.2, 24.3, 21.1, 19.6; IR (diffuse reflectance) 3257 (s), 2992(s), 2946 (s,b), 2906 (s,b), 2849 (s), 2831 (s), 2801 (s), 2774 (s),2676, 2572, 2446, 1463, 1336, 766, 744 (s) cm⁻¹; HRMS (FAB) calcd forC-₁₉H₂₀N₂+H₁277.1704, found 277.1702. Anal. Calcd for C₁₉H₂₀N₂.HCl.0.5EtOAc: C, 72.69; H, 6.80; N, 8.83. Found: C, 72.60; H, 6.82; N, 8.94.

[1212] Preparation 110

[1213] Preparation of3-benzoyl-10-(2-methoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[1214] tert-Butyl10-bromo-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(4.40g, 11.9 mmol), Pd(PPh₃)₄ (1.40 g, 1.21 mmol), and dimethoxyethane(60 mL) were stirred at room temperature for 15 minutes then treatedwith 2-methoxyboronic acid (2.18 g, 14.3 mmol) and a 2 M solution ofNa₂CO₃ (36 mL). The reaction was heated to reflux for 17.0 hours thencooled to room temperature and partitioned between ethyl acetate andwater. The aqueous layer was extracted with ethyl acetate (2×) and theorganic layers were combined, washed with brine, dried over MgSO₄ andconcentrated in vacuo to give a brown foam which was passed through acolumn of silica gel with 40% ethyl acetate/hexane to give 3.87 g (82%)of a white solid as the title compound: mp 218.9-221.6° C. ¹H NMR (400MHz, DMSO-d₆) δ10.95-10.85 (m, 1 H), 7.43-7.38 (m, 4 H), 7.27-7.23 (m, 2H), 7.17-6.97 (m, 4 H), 6.67-6.61 (m, 3.82 (m, 1 H), 3.66-3.53 (m, 5 H),3.27 (m, 1 H), 3.09-3.06 (m, 1 H), 2.85 (m, 1 H), 2.39-2.32 (m, 1 H),2.17-2.13 (m, 1 H); ¹³C NMR (100 MHz, DMSO-d₆) δ170.1, 169.8, 156.8,156.7, 137.1, 135.7, 134.8, 134.6, 130.8, 130.5, 130.4, 130.2, 130.0,128.9, 128.5, 128.3, 128.2, 126.1, 126.0, 120.5, 119.9, 119.8, 119.7,111.2, 110.5, 110.2, 109.7, 109.5, 54.9, 54.7, 49.6, 48.3, 46.1, 44.2,29.4, 27.5, 25.7, 24.6; IR (diffuse reflectance) 3202, 3181 (b), 1602(s), 1500, 1489, 1466, 1434, 1299, 1266, 1249, 1241, 786, 759 (s), 748,707 cm⁻¹; HRMS (FAB) calcd for C₂₆H₂₄N₂O₂+H₁ 397.1916, found 397.1910.Anal. Calcd for C₂₆H₂₄N₂O₂: C, 78.76; H, 6.10; N, 7.07. Found: C, 78.40;H, 6.22; N, 6.97.

Example 325

[1215] 10-(2-Methoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[1216] The3-benzoyl-10-(2-methoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(1.10 g, 2.8 mmol), potassium hydroxide (3.71 g, 57.5 mmol), andethylene glycol (30 mL) were heated to 170° C. for 4 hours. The reactionwas diluted with water and extracted with ethyl acetate (3×). Theorganic layers were combined, washed with brine, dried over MgSO₄ andconcentrated in vacuo to give a brown oil (2.76 g) which was passedthrough a column of silica gel with 1:19 methanol/chloroform with 1%NH₄OH to give a yellow powder 381 mg (47%) which was treated with asolution of 4 N HCl in dioxane (5 mL) and stirred at room temperaturefor 2.3 hours. After the reaction mixture was concentrated in vacuoCH₂Cl₂ was added and the solution was concentrated in vacuo to give awhite solid which was recrystallized from CH₃OH EtOAc to give 0.40 g(43%) of a white solid as the title compound: mp 281.4-283.9° C. ¹H NMR(400 MHz, DMSO-d₆ ) δ11.15 (s, 1 H), 9.40 (br s, 1 H), 7.41-7.36 (m, 1H), 7.26 (d, J=8.0 Hz, 1 H), 7.15 (dd, J=7.4 Hz, 1.7 Hz, 1 H), 7.07-6.99(m, 3 H), 6.69 (d, J=7.6Hz, 1 H), 3.65 (s, 3 H), 3.26 (m, 2 H),3.17-3.14 (m, 2 H), 3.01 (m, 2 H), 2.56-2.39 (m, 2 H); ¹³C NMR (100 MHz,DMSO-d₆ ) δ156.7, 135.2, 134.4, 130.9, 130.0, 129.9, 128.6, 125.5,120.7, 120.0, 110.5, 110.3, 110.0, 54.9, 45.9, 44.3, 24.3, 21.2; IR(diffuse reflectance) 3373 (s), 2958, 2935, 2895, 2832, 2791, 2770,2727, 1483, 1459 (s), 1415, 1230 (s), 1024, 762 (s), 757 (s) cm⁻¹; HRMS(FAB) calcd for C₁₉H₂₀N₂O₁+H₁ 293.1654, found 293.1658.

[1217] Preparation 111

[1218] Preparation of2-(3-Benzoyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)phenol

[1219] A 0° C. solution of3-benzoyl-10-(2-methoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(936 mg, 2.36 mmol) in CH₂Cl₂ (20 mL) was treated with BBr₃ (0.75 mL,7.94 mmol). The reaction was stirred at room temperature under nitrogenfor 16.5 hours. The reaction was cooled to 0°C. and slowly quenched withsaturated NH₄Cl solution. After stirring at room temperature for 1.7hours the reaction was extracted with CH₂Cl₂. The organic layer wasdried over MgSO₄ and concentrated in vacuo to give 792 mg (88%) of ayellow foam as the title compound: MS m/z 383.3 (M⁺+H).

[1220] Preparation 112

[1221] Preparation of3-Benzoyl-10-(2-propoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[1222] A slurry of2-(3-benzoyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)phenol (357mg, 0.93 mmol), CS₂CO₃ (1.24 g, 3.82 mmol) and 1-iodopropane (195 mg,1.15 mmol) in acetone (10 mL) was stirred at room temperature undernitrogen for 15 hours. The reaction was filtered and the filtrateconcentrated in vacuo. The residue was partitioned between ethyl acetateand water. The organic layer was washed with brine, dried over MgSO₄ andconcentrated in vacuo to give a yellow oil which was passed through acolumn of silica gel with 50% ethyl acetate/hexane to give 276 mg (70%)of a white foam as the title compound: MS m/z 425.3 (M⁺+H).

Example 326

[1223] 10-(2-Propoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[1224] The3-benzoyl-10-(2-propoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(1.32 g, 3.1 mmol), potassium hydroxide (4.01 g, 62.2 mmol), andethylene glycol (30 mL) were heated to 170° C. for 3.25 hours. Thereaction was diluted with water and extracted with ethyl acetate (2×).The organic layers were combined, washed with brine, dried over MgSO₄and concentrated in vacuo to give a brown oil (2.79 g) which was passedthrough a column of silica gel with 1:19 methanol/chloroform with 1%NH₄OH to give 747 mg (75%) of a yellow foam as the title compound: ¹HNMR (400 MHz, DMSO-d₆ ) δ10.65 (s, 1 H), 7.33-7.28 (m, 1H), 7.17 (d,J=7.3 Hz, 1 H), 7.11 (dd, J=7.3 Hz, 1.7 Hz), 7.01 (d, J=8.1 Hz, 1 H),6.97-6.92 (m, 2 H), 6.63 (d, J=7.1 Hz, 1 H), 3.88-3.76 (m, 2 H),2.86-2.78 (m, 4 H), 2.59-2.53 (m, 2 H), 2.25-2.11 (m, 2 H), 1.47-1.40(m, H), 0.69 (t, J=7.4 Hz, 3 H); ¹³C NMR (100 MHz, DMSO-d₆ ) δ156.2,137.6, 134.4, 131.0, 130.9, 130.0, 128.2, 126.5, 120.2, 119.7, 119.0,112.6, 111.5, 109.4, 68.8, 49.8, 47.9, 32.0, 28.4, 21.9, 10.0; IR(diffuse reflectance) 3399, 3055, 2961, 2932, 2906 (b), 2877, 2834,1484, 1466, 1449, 1416, 1334, 1259, 1234, 751 (s) cm⁻¹. HRMS (FAB) calcdfor C₂₁H₂₄N₂O₃+H₁: 321.1967 found 321.1958.

Example 327

[1225] 10-(2-Fluorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[1226]3-Benzoyl-10-(2-fluorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(3.50 g, 9.1 mmol), potassium hydroxide (11.80 g, 183 mmol), andethylene glycol (80 mL) were heated to 170° C. for 6.6 hours. Thereaction was diluted with water and extracted with ethyl acetate. Theorganic layers were combined, washed with brine, dried over MgSO₄ andconcentrated in vacuo to give a red oil which was passed through acolumn of silica gel with 1:19 methanol/chloroform with 1% NH₄OH to give2.43 g (95%) of a white solid as the title compound: mp 121.8-126.3° C.¹H NMR (400 MHz, CDCl₃) δ8.02 (br s, 1 H), 7.42-7.34 (m, 3 H), 7.26-7.16(m, 3 H), 6.98 (d, J=7.2 Hz, 1 H), 3.16-2.86 (m, 6 H), 2.58-2.53 (m, 1H), 2.46-2.39 (m, 1 H); MS m/z 281.2 (M⁺+H).

Example 328

[1227] 10-(2,4-dichlorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[1228] Prepared according to the procedure used to prepare10-(2-methylphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride, the title compound was obtained: MS (ESI+) m/z 331.3(MH⁺).

Example 329

[1229]3-benzyl-10-(2,4-dichlorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[1230] Prepared according to the procedure used to prepare3-benzyl-7-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole, the titlecompound was obtained: 0.82 g (91%); mp 194-195.5° C.; IR (diffusereflectance) 3404, 1465, 1455, 1419, 1374, 1346, 1334, 1122, 931, 923,821, 808, 753, 738, 699 cm⁻¹; MS (EI) m/z 420 (M+), 420, 302, 300, 288,217, 134, 133, 132, 91, 65; HRMS (FAB) calcd for C₂₅H₂₂Cl₂N₂+H 421.1238,found 421.1233; Anal. Calcd for C₂₅H₂₂Cl₂N₂: C, 71.26; H, 5.26; N, 6.65;Cl, 16.83, found: C, 71.62; H, 5.38; N, 6.56.

Example 33010-(4-methoxy-2-methylphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[1231]

[1232] Prepared according to the procedure used to prepare9-(4-methoxyphenyl)-1,2,3,4,5,6-haxahydroazepino[4,5-b]indolehydrochloride, the title compound was obtained: 0.60 g (100%); mp >262°C. (dec.); IR (diffuse reflectance) 3241, 3053, 2955, 2831, 2806, 2769,2739, 2671, 2642, 1607, 1491, 1458, 1291, 1238, 753 cm⁻¹; MS (EI) m/z306 (M+), 291, 277, 265, 264, 249, 248, 234, 218, 204; HRMS (FAB) calcdfor C₂₀H₂₂N₂O+H 307.1810, found 307.1801; Anal. Calcd for C₂₀H₂₂N₂O.HCl:C, 70.06; H, 6.76; N, 8.17; Cl, 10.34; found: C, 70.09; H, 6.90; N,8.17.

Example 331

[1233]3-benzyl-10-(4-methoxy-2-methylphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[1234] Prepared according to the procedure used to prepare3-benzyl-7-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole, the titlecompound was obtained: 0.81 g (97%); mp 177-178° C.; IR (diffusereflectance) 3406, 2813, 1607, 1513, 1490, 1454, 1346, 1332, 1318, 1237,1175, 1121, 930, 754, 743 cm⁻¹; MS (EI) m/z 396 (M⁺), 276, 264, 134,100, 91, 77, 60, 57, 55; HRMS (FAB) calcd for C₂₇H₂₈N₂O+H 397.2280,found 397.2282.

Example 332

[1235] 10-(2-ethoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride

[1236] Prepared according to the procedure used to prepare9-(4-methoxyphenyl)-1,2,3,4,5,6-haxahydroazepino[4,5-b]indolehydrochloride, the title compound was obtained: 0.29 (60%); MS (ESI+)m/z 307.3 (MH⁺).

Example 333

[1237]3-benzyl-10-(2-ethoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[1238] Prepared according to the procedure used to prepare3-benzyl-7-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole, the titlecompound was obtained: 0.84 (89%); ¹H NMR 3400 MHz, CDCl₃) δ7.80,7.40-7.27, 7.22, 7.14, 7.02, 6.94, 3.98, 3.75, 2.90, 2.68, 2.45, 1.19.

Example 334

[1239] 9-pyridin-4-yl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole formate

[1240] In a 20 mL vial a solution of MeOH/dioxane (10%, 1.5 mL, degassedwith N₂) was added to a mixture of3-(tert-butyloxycarbonyl)-9-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(0.097 g, 0.235 mmol), cesium carbonate (0.115 g, 0.35 mmol), and4-bromopyridine hydrochloride (0.137g, 0.70 mmol) anddiphenylphosphinoferrocene (0.07 g, 5 mol %) were added. The mixture wasflushed with argon and tris(dibenzylideneacetone)dipalladium (0) (0.06g, 3 mol %) was added and the vial was placed on a shaker heated at 90°C. for 18 h. Equivalent amounts of cesium carbonate and the palladiumcatalyst were added with a small amount of MeOH for solubility, and thevial was returned to the shaker and heated at 90° C. for 48 h. MeOH andBio-Rad Ag. 50W-X2 resin (0.8 g, 5.2 meq, 18 equivalents) were added andheated on the shaker at 65° C. for 2 h. The mixture was rinsed into afritted plastic syringe and was washed with: MeOH, water, 2 N pyridinein MeOH, THF, MeOH, THF and finally CH₂Cl₂. The resulting cake of resinwas then washed with 4 M NH4OH/MeOH and THF successively into taredvials, which were concentrated down on a Genevac for 18 h. The productwas purified on a reverse phase HPLC system to give 4.3 mg (7%) of thetitle compound as the formate salt. MS (EI) m/z 264 (MH+).

Example 335

[1241] 10-(2-Butoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[1242] Following the procedure for10-(2-propoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole andsubstituting 1-iodobutane for 1-iodopropane while making non-criticalvariations the title compound was obtained as 128 mg (50%) of a brownoil: ¹H NMR (400 MHz, CDCl₃) δ7.94 (br s, 1 H), 7.37-7.30 (m, 2 H), 7.25(dd, J=8.0 Hz, 0.9 Hz, 1 H), 7.17-7.13 (m, 1 H), 7.05-7.04 (m, 1 H),6.99 (d, J=8.2 Hz, 1 H), 6.95-6.93 (m, 1 H), 3.96-3.87 (m, 2 H),3.11-3.00 (m, 2 H), 2.96-2.81 (m, 4 H), 2.44-2.39 (m, 2 H), 1.59-1.51(m, 2 H), 1.27-1.17 (m, 2 H), 0.80 (t, J=7.4 Hz, 3 H); HRMS (FAB) calcdfor C₂₂H₂₆N₂O+H₁: 335.2123 found 335.2137.

Example 336

[1243]10-[2-(Cyclopropylmethoxy)phenyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[1244] Following the procedure for the preparation of10-(2-propoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole andsubstituting (bromomethyl)cyclopropane for 1-iodopropane while makingnon-critical variations the title compound was obtained as 74 mg (14%)of a brown oil: ¹H NMR (400 MHz, CDCl₃) δ7.92 (br s, 1 H), 7.29-7.21 (m,2 H), 7.12 (d, J=8.0 Hz, 1 H), 7.07-7.03 (m, 1 H), 6.98-6.94 (m, 1 H),6.92 (d, J=8.2 Hz, 1 H), 6.86 (d, J=7.1 Hz, 1 H), 3.70 (d, J=6.3 Hz, 2H), 3.01-2.95 (m, 2 H), 2.85-2.73 (m, 4 H), 2.37-2.31 (m, 2 H),0.95-0.93 (m, 1 H), 0.30-0.25 (m, 2 H), 0.00-(−0.03) (m, 2 H); HRMS(FAB) calcd for C₂₂H₂₄N₂O+H₁: 333.1967 found 333.1955.

Example 337

[1245]10-[2-(Pentyloxy)phenyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[1246] Following the procedure for the preparation of10-(2-propoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole andsubstituting 1-iodopentane for 1-iodopropane while making non-criticalvariations the title compound was obtained as 361 mg (71%) of a brownoil: ¹H NMR (400 MHz, CDCl₃) δ7.83 (br s, 1 H), 7.36-7.28 (m, 3 H),7.17-7.13 (m, 1 H), 7.05-7.01 (m, 1 H), 6.97 (d, J=8.2 Hz, 1 H), 6.93(d, J=7.2 Hz, 1 H), 3.95-3.85 (m, 2 H), 3.12-3.10 (m, 1 H), 3.06-3.04(m, 1 H), 2.98-2.93 (m, 2 H), 2.88-2.85 (m, 1 H), 2.81-2.79 (m, 1 H),2.42-2.37 (m, 2 H), 1.59-1.52 (m, 2 H), 1.21-1.13 (m, 4 H), 0.79 (t,J=7.0 Hz, 3 H); HRMS (FAB) calcd for C₂₃H₂₈N₂O+H₁: 349.2280 found349.2280.

Example 338

[1247] 10-[2-(Hexyloxy)phenyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[1248] Following the procedure for the preparation of10-(2-propoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole andsubstituting 1-iodohexane for 1-iodopropane while making non-criticalvariations the title compound was obtained as 360 mg (66%) of a yellowfoam: ¹H NMR (400 MHz, CDCl₃) δ7.83 (br s, 1 H), 7.36-7.27 (m, 3 H),7.17-7.13 (m, 1 H), 7.05-7.01 (m, 1 H), 6.98 (d, J=8.2 Hz, 1 H), 6.93(d, J=7.2 Hz, 1 H), 3.95-3.85 (m, 2 H), 3.12-3.10 (m, 1 H), 3.06-3.01(m, 1 H), 2.98-2.93 (m, 2 H), 2.90-2.85 (m, 1 H), 2.82-2.79 (m, 1 H),2.42-2.37 (m, 2 H), 1.57-1.51 (m, 2 H), 1.22-1.16 (m, 6 H), 0.83 (t,J=6.9 Hz, 3 H); HRMS (FAB) calcd for C₂₄H₃₀N₂O+H₁: 363.2436 found363.2444.

Example 339

[1249] 10-(2-Isopropoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[1250] Following the procedure for the preparation of10-(2-propoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole andsubstituting 2-iodopropane for 1-iodopropane while making non-criticalvariations the title compound was obtained as 236 mg (56%) of a brownoil: ¹H NMR (400 MHz, CDCl₃) δ7.88 (br s, 1 H), 7.36-7.26 (m, 3 H),7.16-7.12 (m, 1 H), 7.05-7.00 (m, 2 H), 6.95 (d, J=7.2 Hz, 1 H),4.33-4.27 (m, 1 H), 3.11-3.03 (m, 2 H), 2.96-2.94 (m, 2 H), 2.87-2.81(m, 2 H), 2.48-2.35 (m, 2 H), 1.15-1.08 (m, 6 H); HRMS (FAB) calcd forC₂₁H₂₄N₂O+H₁: 321.1967 found 321.1949.

[1251] Preparation 113

[1252] Preparation of3-Benzoyl-10-[2-(cyclopentyloxy)phenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[1253] A 0° C. solution of2-(3-benzoyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-yl)phenol (0.88mg, 2.30 mmol) in THF (5 mL) was treated with triphenylphosphine (1.03g, 3.93 mmol) and cyclopentanol (0.32 g, 3.67 mmol). After stirring for10 minutes, di-tert-butyl azodicarboxylate (0.80 g, 3.45 mmol) was addeddropwise and the reaction was stirred at room temperature for 16.5hours. The reaction mixture was concentrated in vacuo, dissolved inCH₂Cl₂ and passed through a column of silica gel with 50% ethylacetate/hexane to give 741 mg (72%) of a yellow solid as the titlecompound: mp 187.0-189.2° C. MS m/z 451.3 (M⁺+H).

Example 340

[1254]10-[2-(Cyclopentyloxy)phenyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[1255] The3-benzoyl-10-[2-(cyclopentyloxy)phenyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(0.73 g, 1.6 mmol), potassium hydroxide (2.07 g, 32.1 mmol), andethylene glycol (15 mL) were heated to 170° C. for 2.67 hours. Thereaction was diluted with water and extracted with ethyl acetate (233).The organic layers were combined, washed with brine, dried over MgSO₄and concentrated in vacuo to give a brown oil which was passed through acolumn of silica gel with 3% methanol/chloroform with 1% NH₄OH to give419 mg (74%) of a white foam as the title compound: ¹H NMR (400 MHz,CDCl₃) δ7.83 (br s, 1 H), 7.35-7.26 (m, 3 H), 7.15-7.11 (m, 1 H),7.03-6.96 (m, 2 H), 6.91 (d, J=7.2 Hz, 1 H), 4.69-4.65 (m, 1 H),3.11-3.07 (m, 2 H), 2.99-2.95 (m, 2 H), 2.87-2.81 (m, 2 H), 2.45-2.39(m, 2 H), 1.73-1.67 (m, 4 H), 1.48-1.45 (m, 4 H); HRMS (FAB) calcd forC₂₃H₂₆N₂O+H₁: 347.2123 found 321.2134.

Example 341

[1256]10-[2-(Cyclohexyloxy)phenyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[1257] Following the procedure for the preparation of(5aS*,10bS*)-10-[2-(cyclopentyloxy)phenyl]-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indoleand substituting cyclohexanol for cyclopentanol while makingnon-critical variations the title compound was obtained as 278 mg (32%)of a white foam: ¹H NMR (400 MHz, CDCl₃) δ7.84 (br s, 1 H), 7.35-7.26(m, 3 H), 7.15-7.11 (m, 1 H), 7.04-7.01 (m, 2 H), 6.95 (d, J=7.2 Hz, 1H), 4.08-4.06 (m, 1 H), 3.09-3.07 (m, 2 H), 2.97-2.96 (m, 2 H),2.85-2.83 (m, 2 H), 2.47-2.37 (m, 2 H), 1.90 (m, 2 H) 1.71 (m, 2 H),1.51 (m, 2 H), 1.41 (m, 2 H), 1.15 (m, 3 H); HRMS (FAB) calcd forC₂₄H₂₈N₂O+H₁: 361.2280 found 361.2270.

Example 342

[1258]10-[2-(Cyclobutyloxy)phenyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[1259] Following the procedure for the preparation of(5aS*,10bS*)-10-[2-(cyclopentyloxy)phenyl]-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indoleand substituting cyclobutanol for cyclopentanol while makingnon-critical variations the title compound was obtained as 193 mg (37%)of a tan solid: mp 182.0-184.5° C. ¹H NMR (400 MHz, CDCl₃) δ7.85 (br s,1 H), 7.35-7.28 (m, 3 H), 7.18-7.14 (m, 1 H), 7.04-7.00 (m, 1 H), 6.94(d, J=7.2 Hz, 1 H), 6.84 (d, J=8.2 Hz, 1 H), 4.63-4.56 (m, 1 H),3.10-3.07 (m, 2 H), 2.98-2.95 (m, 2 H), 2.87-2.84 (m, 2 H), 2.47-2.41(m, 2 H), 2.37-2.32 (m, 2 H), 2.02-2.00 (m, 2 H), 1.74-1.72 (m, 1 H),1.64-1.59 (m, 1 H); HRMS (FAB) calcd for C₂₂H₂₄N₂O+H₁: 333.1967 found333.1960.

[1260] Preparation 114

[1261] Preparation of tert-butyl10-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[1262] tert-Butyl10-bromo-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (1.51g, 4.12 mmol) and dioxane (26 mL) were combined at rt under N₂. Et₃N(3.43 mL, 2.49 g, 24.6 mmol) and 4,4,5,5-tetramethyl-1,3,2-dioxaborolan(1.28 mL, 1.05 g, 8.21 mmol) were added to the mixture by syringe.trans-Dichlorobis(triphenylphosphine)palladium(II) (0.147 g, 0.209 mmol)was added and Ar was bubbled through the reaction mixture for 15 min.The reaction mixture was refluxed under N₂ for 16 h. The cooled reactionmixture was concentrated and the residue was combined with toluene (50mL), brine (20 mL) and H₂O (100 mL). The layers were separated and theaqueous layer was extracted with toluene (2×50 mL). The combined organicextracts were washed with brine (40 mL), dried over MgSO₄, filtered andconcentrated. The crude product (1.90 g) was chromatographed (SiO₂ 60 g,eluted with 2:2:1 heptane:CH₂Cl₂:Et₂O) to give tert-butyl10-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(1.57 g) in 93% yield. MS (ESI+) for C₂₃H₃₃BN₂O₄ m/z 413.2 (M+H)⁺.

[1263] Preparation 115

[1264] Preparation of tert-butyl10-(2,6-difluorophenyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate

[1265] Prepared according to the procedure used to prepare tert-butyl9-(2,6-difluorophenyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylatein 58% yield. MS (ESI+) for C₂₃H₂₄F₂N₂O₃ m/z 399.0 (M+H)⁺.

Example 343

[1266] 10-(2,6-difluorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[1267] tert-Butyl10-(2,6-difluorophenyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.700 g, 1.76 mmol) was dissolved in CF₃CO₂H (4 mL) and CH₂Cl₂ (14 mL)and the reaction mixture was stirred at rt for 3 h. The reaction mixturewas cooled in an ice bath and quenched with cold 1N NaOH (100 mL). Theresulting mixture was extracted with 3% CH₃OH in CH₂Cl₂ (3×50 mL). Thecombined organic extracts were dried over Na₂SO₄, filtered andconcentrated. The crude product (0.51 g) was chromatographed (SiO₂ 30 g,eluted with 90:10:1 CH₂Cl₂:CH₃OH:conc. NH₄OH) to yield10-(2,6-difluorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.458g) in 87% yield. ¹H NMR (400 MHz, Acetone-d₆) δ2.35-2.38, 2.74-2.77,2.95-2.98, 6.84, 7.08, 7.12, 7.36, 7.50; MS (ESI+) for C₁₈H₁₆F₂N₂ m/z299.1 (M+H)⁺.

[1268] Preparation 116

[1269] Preparation of3-benzoyl-10-[2-(trifluoromethoxy)phenyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[1270] 3-Benzoyl-10-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(4.00 g, 10.8 mmol) was suspended in benzene (170 mL).2-(Trifluoromethoxy)-phenylboronic acid (4.48 g, 21.7 mmol),trans-dichlorobis(triphenylphosphine)palladium(II) (0.433 g, 0.617 mmol)and 2M Na₂CO₃ (17.6 mL) were added to the reaction mixture. Ar wasbubbled through the reaction mixture for 20 min. The reaction mixturewas heated at reflux for 11 h. After cooling, the reaction mixture wasconcentrated. The residue was combined with EtOAc (250 mL) and H₂O (400mL). The layers were separated and the aqueous layer was extracted withEtOAc (2×100 mL). The combined organic layers were dried over MgSO₄,filtered and concentrated. The crude product (7.95 g) was recrystallizedfrom CH₃OH to yield3-benzoyl-10-[2-(trifluoromethoxy)phenyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(1.43 g). The crude product from the mother liquors was chromatographed(SiO₂ 250 g, eluted with 2:1 toluene:EtOAc) to give3-benzoyl-10-[2-(trifluoromethoxy)phenyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(5.21 g). The yield of the reaction was 87%. IR (diffuse reflectance)3266, 3227, 3187, 1615, 1574, 1498, 1483, 1464, 1428, 1382, 1354, 1334,1323, 1288, 1253, 1221, 1202, 1167, 926, 790, 767, 750, 732, 704, 626cm⁻¹; MS (ESI+) for C₂₆H₂₁F₃N₂O₂ m/z 450.9 (M+H)⁺; Anal. Calcd forC₂₆H₂₁F₃N₂O₂: C, 69.32; H, 4.70; N, 6.22; found: C, 69.25; H, 4.78; N,6.25.

Example 344

[1271]10-[2-(trifluoromethoxy)phenyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[1272]3-Benzoyl-10-[2-(trifluoromethoxy)phenyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(1.55 g, 3.44 mmol) and ethylene glycol (50 mL) were combined and heatedto 170° C. KOH (3.91 g, 69.7 mmol) was added and the reaction mixturewas stirred at 170° C. for 1.5 h. The reaction mixture was cooled to rtand was combined with EtOAc (100 mL) and H₂O (300 mL). The layers wereseparated and the aqueous layer was extracted with EtOAc (2×100 mL). Thecombined organic layers were dried over MgSO₄, filtered and concentratedto give crude product (5.22 g). The crude product was chromatographed(SiO₂ 100 g, eluted with 90:10:1 CH₂Cl₂:CH₃OH:conc. NH₄OH) to give10-[2-(trifluoromethoxy)phenyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(0.82 g) in 69% yield. ¹H NMR (400 MHz, CD₃OD) δ2.24-2.36, 2.70-2.76,2.95-3.03, 6.75, 7.06, 7.30, 7.36-7.42, 7.46-7.51; MS (ESI+) forC₁₉H₁₇F₃N₂O m/z 347.2 (M+H)⁺.

[1273] Preparation 117

[1274] Preparation of3-benzoyl-10-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[1275] 3-Benzoyl-10-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(15.0 g, 40.6 mmol) was combined with dioxane (350 mL) at rt under N₂.Et₃N (34.0 mL, 24.7 g, 244 mmol) and4,4,5,5-tetramethyl-1,3,2-dioxaborolane (11.4 mL, 9.37 g, 73.2mmol) wereadded to the mixture by syringe.trans-Dichlorobis(triphenylphosphine)palladium(II) (1.44 g, 2.04 mmol)was added and Ar was bubbled through the reaction mixture for 20 min.The reaction mixture was refluxed under N₂ for 18 h. The cooled reactionmixture was concentrated and the residue was combined with EtOAc (500mL) and H₂O (200 mL). The layers were separated and the aqueous layerwas extracted with EtOAc (2×100 mL). The combined organic extracts weredried over MgSO₄, filtered and concentrated. The crude product (22.9 g)was recrystallized from CH₃OH (50 mL) to give3-benzoyl-10-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(11.7 g) in 69% yield. MS (ESI+) for C₂₅H₂₉BN₂O₃ m/z 417.2 (M+H)⁺.

[1276] Preparation 118

[1277] Preparation of3-benzoyl-10-[2-(trifluoromethyl)phenyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[1278]3-Benzoyl-10-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(2.50 g, 6.00 mmol), triturated potassium phosphate (3.01 g, 14.2 mmol)and tris(dibenzylideneacetone)dipalladium(0) (0.562 g, 0.613 mmol) werecombined in dioxane (63 mL) at rt under N₂. 2-Bromobenzotrifluoride(0.98 mL, 1.62 g, 7.21 mmol) and trimethylphosphite (0.22 mL, 0.231 g,1.86 mmol) were added to the reaction mixture by syringe. Ar was bubbledthrough the reaction mixture for 20 min. The reaction mixture was heatedto reflux for 22 h. The reaction mixture was concentrated and theresidue was taken up in toluene (150 mL) and H₂O (200 mL). The layerswere separated and the aqueous layer was extracted with toluene (1×100mL, 1×50 mL). The combined organic layers were dried over MgSO₄,filtered and concentrated. The crude product (3.90 g) waschromatographed (SiO₂ 250 g, eluted with 2:1 toluene:EtOAc) to yield3-benzoyl-10-[2-(trifluoromethyl)phenyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(2.48 g) in 95% yield. IR (diffuse reflectance) 3294, 1617, 1575, 1461,1439, 1423, 1346, 1334, 1316, 1276, 1266, 1259, 1178, 1170, 1126, 1113,1105, 1058, 1034, 792, 775, 755, 719, 701, 626 cm⁻¹; MS (ESI+) forC₂₆H₂₁F₃N₂O m/z 435.0 (M+H)⁺; Anal. Calcd for C₂₆H₂₁F₃N₂O: C, 71.88: H,4.87: N, 6.45: found: C, 71.94: H, 4.93: N, 6.48.

Example 345

[1279]10-[2-(trifluoromethyl)phenyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[1280] Prepared according to the procedure used to prepare10-[2-(trifluoromethoxy)phenyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolein 69% yield. ¹H NMR (400 MHz, CD₃OD) δ2.02-2.14, 2.64, 2.71, 2.93-3.03,6.72, 7.02, 7.29, 7.34, 7.56, 7.61, 7.78: MS (ESI+) for C₁₉H₁₇F₃N₂ m/z331.1 (M+H)⁺.

[1281] Preparation 119

[1282] Preparation of3-benzoyl-10-(4-chlorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[1283]10-bromo-1,4,5,6-tetrahydroazepino[4,5-b]indol-3(2H)-yl](phenyl)methanone(500 mg), 4-chlorophenyl boronic acid (423 mg) andtrans-dichlorobis(triphenylphosphine)palladium (II) (52 mg) weredissolved in benzene (42 ml) and 2N Na₂CO₃ (3.3 ml). The reactionmixture was heated at 80° C. for 20 h, poured into brine, extracted withEtOAc, dried over MgSO₄, filtered and concentrated. Purification viaflash chromatography (silica gel, 1:1 hexane:EtOAc) provided 520 mg ofthe title compound as a solid: ¹H NMR (DMSO-d₆) δ1.99, 2.49, 3.12, 3.53,3.62, 3.84, 6.77, 7.02, 7.4-7.6.

Example 346

[1284] 10-(4-chlorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indoledihydrochloride

[1285]3-benzoyl-10-(4-chlorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indoleand KOH (3.0 g) were stirred in ethylene glycol (10 ml) and the reactionmixture was heated at 170° C. for 1 h. The reaction mixture was cooledto RT, partitioned between H₂O and EtOAc, separated, dried over MgSO₄,filtered and concentrated. The product was dissolved in EtOAc and HCl (4ml, 1N in Et₂O) was added. The precipitate was filtered andrecrystallized from EtOAc/MeOH to give the title compound as a solid: ¹HNMR (DMSO-d₆) δ3.09, 3.18, 3.30, 4.48, 6.78, 7.08, 7.32, 7.38, 7.52,9.60, 11.3. HRMS (FAB) calcd for C₁₈H₁₇ClN₂ (MH⁺) 297.1158, found297.1137.

[1286] Preparation 120

[1287] Preparation of3-benzoyl-10-(3-chlorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[1288] Following the procedure for the preparation of3-benzoyl-10-(4-chlorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,making non-critical variations, starting with the appropriate boronicacid , the title compound was obtained. ¹H NMR (DMSO-d₆) δ2.24, 2.49,2.89, 3.12, 3.52, 3.59, 3.84, 6.77, 7.06, 7.31-7.47, 11.23. HRMS (FAB)calcd for C₂₅H₂₁ClN₂O (MH⁺) 401.1420, found 401.1396.

Example 347

[1289] 10-(3-chlorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indoledihydrochloride

[1290] Following the procedure for the preparation of10-(4-chlorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride, making non-critical variations, starting with3-benzoyl-10-(3-chlorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,the title compound was obtained. ¹H NMR (DMSO-d₆) δ3.05, 3.21, 3.31,4.51, 6.85, 7.1-7.5, 11.3.

[1291] Preparation 121

[1292] Preparation of3-benzoyl-10-(2,4-dichlorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[1293] Following the procedure for the preparation of3-benzoyl-10-(4-chlorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,making non-critical variations, starting with the appropriate boronicacid , the title compound was obtained: ¹H NMR (DMSO-d₆) ι1.99, 2.2-2.4,2.87, 3.11, 3.53, 3.82, 6.69, 7.06, 7.27-7.75, 7.06.

[1294] Preparation 122

[1295] Preparation of tert-butyl10-(2,4-dichlorophenyl)-1,4,5,5a,6,10b-hexahydroazepino[4,5-b]indole-3(2H)-carboxylate

[1296] 10-(2,4-dichlorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(610 mg) was dissolved in TFA (12 ml), and sodium cyanoborohydride (589mg)was added portionwise. The reaction mixture stirred 2 h, was quenchedwith 2N NaOH, extracted with EtOAc, dried over MgSO₄, filtered andconcentrated. The crude product was dissolved in THF (14 ml) with 2NNa₂CO₃ (4.6 ml) and Boc₂O (441 mg) was added. The reaction mixture wasstirred 1 h, poured into brine, extracted with CH₂Cl₂, dried over MgSO₄,filtered and concentrated. Purification via flash chromatography (silicagel, 3:1 hexanes:EtOAc) provided the title compound (660 mg): ¹H NMR(CD₃OD) δ1.39, 1.44, 1.99, 3.2-3.6, 6.46, 6.65, 7.05, 7.32, 7.39, 7.41,7.57.

[1297] Preparation 123

[1298] Preparation of tert-butyl10-(2,4-dichlorophenyl)-6-(2-phenoxyethyl)-1,4,5,5a,6,10b-hexahydroazepino[4,5-b]indole-3(2H)-carboxylate

[1299] To a solution of tert-butyl10-(2,4-dichlorophenyl)-1,4,5,5a,6,10b-hexahydroazepino[4,5-b]indole-3(2H)-carboxylate(54 mg) in DMF (1.2 ml) was added KH (10 mg) and 2-bromoethyl phenylether (30 mg). The reaction mixture was stirred 24 h, poured into satdNaHCO3, extracted with CH₂Cl₂, dried over MgSO₄, filtered andconcentrated. Purification via flash chromatography provided the titlecompound: ¹H NMR (CDCl₃) δ1.63, 2.30-2.50, 2.92, 3.14, 3.42, 3.75, 4.26,4.53, 6.84, 6.96, 7.20-7.51.

Example 348

[1300]10-(2,4-dichlorophenyl)-6-(2-phenoxyethyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[1301] To a solution of 1-tert-butyl10-(2,4-dichlorophenyl)-1,4,5,5a,6,10b-hexahydroazepino[4,5-b]indole-3(2H)-carboxylate(50 mg) in CH₂Cl₂ (2 ml) was added TFA (0.25 ml). The reaction mixturestirred 2 h, was quenched with 2N NaOH, extracted with EtOAc, dried overMgSO₄, filtered and concentrated. Purification via flash chromatography(silica gel, 9:1 CH₂Cl₂/MeOH with 0.5% NH₄OH) provided the titlecompound: ¹H NMR (CD₃OD) δ2.25-2.43, 2.72, 3.03, 3.33, 4.21, 4.55, 6.75,6.87, 7.14, 7.17. HRMS (FAB) calcd for C₂₆H₂₄Cl₂N₂O₂ (MH⁺) 451.1344,found 451.1340.

Example 349

[1302] N-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-amine

[1303] To a solution of tert-butyl10-bromo-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (600mg), sodium t-butoxide (220 mg), tris(dibenzylideneacetone) dipalladium(23 mg), aniline (183 mg) toluene (1.64 ml) was added2-(di-t-butylphosphino)biphenyl (30 mg) and the reaction mixture washeated at 50° C. The reaction mixture stirred 16 h, was poured intobrine, extracted with CH₂Cl₂, dried over MgSO₄, filtered andconcentrated. The crude product was stirred in CH₂Cl₂ (8 ml) and TFA (2ml) was added. The reaction mixture stirred 1 h, was quenched with 2NNaOH, extracted with CH₂Cl₂, dried over MgSO₄, filtered andconcentrated. Purification via flash chromatography (silica gel,CH₂Cl₂/MeOH, 9/1 with 0.5% NH₄OH) provided the title compound: ¹H NMR(DMSO-d₆) δ2.68, 2.83-2.90, 6.58-6.67, 6.89, 7.06, 7.54, 10.71.

Example 350

[1304]N-(2-chlorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-amine

[1305] Following the procedure for the preparation ofN-phenyl-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-amine, makingnon-critical variations, starting from tert-butyl10-bromo-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate thetitle compound was prepared: ¹H NMR (DMSO-d₆) δ2.91, 3.01, 3.06, 3.20,6.36, 6.65, 6.75, 6.99, 7.17, 7.35, 11.0. HRMS (FAB) calcd forC₁₈H₁₈ClN₃ (MH⁺) 312.1267, found 312.1281.

Examples 351-465

[1306] Preparation 124

[1307] Preparation of8,9-dichloro-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[1308] A mixture of3-benzoyl-8,9-dichloro-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (2.00g, 5.57 mmol), potassium hydroxide (3.00 g, 53.5 mmol), and ethyleneglycol (15 mL) was heated to 170° C. After 2 h, the reaction was cooledto room temperature, diluted with H₂O, and extracted with CH₂Cl₂. Thecombined organic extracts were washed with brine, dried over Na₂SO₄,decanted, and concentrated under reduced pressure. The crude product waspurified by silica gel chromatography with CH₂Cl₂/MeOH/Et₂NH (9:1:0followed by 97:3:1 followed by 95:4:1) to give 1.04 g (73%) of8,9-dichloro-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole as a dark yellowsolid. ¹H NMR (d-CHCl₃) δ7.75, 7.50, 7.34, 3.08, 2.92, 2.82, 1.91: MS(ESI) 255.1 (M⁺+H).

Example 351

[1309](5aS*,10bS*)-8,9-dichloro-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1310] A solution of8,9-dichloro-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.40 g, 1.6mmol) in TFA (4.0 mL) was cooled to 0° C., then a freshly preparedsolution of Na(CN)BH₃ (0.49 g, 7.8 mmol) in MeOH (.1.5 mL) was addeddropwise. The ice bath was removed after the addition was complete.After 2.5 h, the reaction was diluted with H₂O, made basic with 50%aqueous NaOH, and extracted with EtOAc. The combined organic extractswere washed with brine, dried over Na₂SO₄, decanted, and concentratedunder reduced pressure. The crude product was purified by silica gelchromatography and prep HPLC to give 0.14 g (36%) of the title compoundas pale orange solid. ¹H NMR (d-CHCl₃) δ7.00, 6.58, 4.22, 3.81, 3.58,3.14-2.98, 2.79, 2.07-1.87: IR (drift) 3201, 3170, 3149, 3031, 2927,2852, 2838, 2750, 1608, 1483, 1450, 1365, 1273, 832, 660 cm⁻¹; HRMS(FAB) calcd for C₁₂H₁₄Cl₂N₂+H 257.0612, found 257.0614.

[1311] Preparation 125

[1312] Preparation of3-benzoyl-8,9-dichloro-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1313] A solution of3-benzoyl-8,9-dichloro-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.25g, 0.70 mmol) in TFA (2.0 mL) was cooled to 0° C., then a freshlyprepared solution of Na(CN)BH₃ (0.22 g, 3.5 mmol) in MeOH (0.75 mL) wasadded dropwise. The ice bath was removed after the addition wascomplete. After 3 h, the reaction was diluted with H₂O, made basic with50% aqueous NaOH, and extracted with EtOAc. The combined organicextracts were washed with brine, dried over Na₂SO₄, decanted, andconcentrated under reduced pressure. The crude product was purified bysilica gel chromatography with EtOAc/heptanes (1:1) to give 0.19 g (76%)of3-benzoyl-8,9-dichloro-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indoleas a yellow foam (mixture of diastereomers). ¹H NMR (d-CHCl₃)δ7.42-7.37, 7.04, 6.95, 6.66-6.61, 4.34-3.07, 2.73, 2.49, 2.23-1.52: MS(ESI) 361.1 (M⁺+H).

Example 352

[1314](5aR*,10bS*)-8,9-dichloro-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1315] A mixture of3-benzoyl-8,9-dichloro-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole(0.20 g, 0.55), potassium hydroxide (1.0 g, 17.8 mmol), and ethyleneglycol (5 mL) was heated to 170° C. Upon the disappearance of startingmaterial, the reaction was cooled to room temperature, diluted with H₂O,and extracted with CH₂Cl₂. The combined organic extracts were washedwith brine, dried over Na₂SO₄, decanted, and concentrated under reducedpressure. The crude product was purified by silica gel chromatographyand prep HPLC to give the title compound (31 mg, 22%) as a tan solid. ¹HNMR (d-MeOH) δ8.54, 7.02, 6.63, 3.73, 3.08-2.88, 2.40, 2.17, 1.81, 1.65:IR (drift) 2934, 2916, 2866, 2850, 2831, 1627, 1608, 1569, 1481, 1466,1372, 1365, 953, 775, 662 cm⁻¹; HRMS (FAB) calcd for C₁₂H₁₄C₁₂N₂+H257.0612, found 257.0619.

Example 353

[1316] (5aS*,10bS*) -1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1317] A solution of 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.93 g,5.0 mmol) in trifluoroacetic acid (17 mL) was cooled to 0° C., andtreated with a freshly prepared solution of Na(CN)BH₃ (1.57 g, 25 mmol)in MeOH (4 mL). The cooling bath was removed and the reaction mixturewas stirred at room temperature for 1 h, then treated with water (75mL), stirred for an additional 15 minutes before adjusting the pH to 14with 45% KOH (aqueous). The resulting solution was extracted with EtOAc(3×40 mL), and the combined organic extracts were washed once withbrine, dried over MgSO₄, filtered, and concentrated in vacuo to give ayellow syrup. The crude product was purified by chromatography and usingethanol:ammonia:dichloromethane (15:1.5:83.5) and trituration of theresulting material gave the title compound (0.64g) as an off-whitesolid: mp 102-114° C.

Example 354

[1318]9-(2,6-Difluorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indoledihydrochloride

[1319] A freshly prepared solution of sodium cyanoborohydride (0.16 g,2.5 mmol) in MeOH (0.75 mL) was added to a solution of9-(2,6-difluorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.15g, 0.50 mmol) in THF (3.0 mL) at 0° C. Upon completion of the addition,the ice bath was removed. After 1 h, the reaction was diluted with H₂O,quenched with 50% aqueous NaOH, and extracted with EtOAc (3×10 mL). Thecombined organic extracts were washed with brine, dried over Na₂SO₄,decanted, and concentrated. The crude product was purified by columnchromatography (Biotage, 40S) with CH₂Cl₂/MeOH/NH₄OH (gradient, 976:21:3to 960:35:5) to give 98 mg of impure amine. The HCl salt was prepared togive 30 mg of a light pink solid: mp 268.5-271.5° C.; IR (diffusereflectance) 2858, 2818, 2792, 2774, 2739, 2678, 2641, 2571, 2550, 2494,2463, 2395, 1464, 990, 800 cm⁻¹; MS (El) m/z 300 (M⁺), 300, 256, 244,243, 242, 229, 78, 64, 63, 61: Anal. Calcd for C₁₈H₁₈F₂N₂.2HCl: C,57.92: H, 5.40: N, 7.51: found: C, 57.63; H, 5.58: N, 7.33.

[1320] Preparation 126

[1321] Preparation of3-Benzoyl-9-(4-methoxy-2-methylphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole.

[1322] A solution of3-benzoyl-9-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1.50 g,4.06 mmol) in DME (50 mL) was degassed via sonication and vacuum/N₂purge. Then, (PhP₃)₄Pd (0.235 g, 0.203 mmol) was added and the mixturewas stirred for 20 min prior to the addition of a solution oftris(4-methoxy-2-methylphenyl)boroxin (0.900 g, 2.03 mmol) in DME (10mL) and MeOH (2.5 mL). Next, 2M Na₂CO₃ (12 mL) was added and thereaction was heated to reflux. After 7 h, additional (PhP₃)₄Pd (0.235 g,0.203 mmol) was added. The reaction was cooled to rt after an additional15 h. The reaction was partitioned between H₂O and EtOAc and the layerswere separated. The aqueous layer was extracted with additional EtOAc(2×100 mL). The combined organic extracts were washed with brine, driedover Na₂SO₄, decanted, and concentrated. The crude product was purifiedby column chromatography (Biotage, 40M) with heptane/EtOAc (gradient,2:1 to 1:1) to give 0.61 (37%) of the title compound. An analyticalsample was prepared, via crystallization from heptane/EtOAc, as anoff-white solid: mp 268.5-271.5° C.; IR (diffuse reflectance) 3297,3250, 3243, 3202, 1608, 1500, 1467, 1430, 1300, 1289, 1276, 1233, 786,740, 706 cm⁻¹; MS (EI) m/z 410 (M⁺), 290, 289, 288, 276, 105, 86, 77,51, 50: HRMS (FAB) calcd for C₂₇H₂₆N₂O₂+H 411.2072, found 411.2073: %water (KF): 0.23: melt solvate: 1.91% EtOAc, 0.15% heptane; Anal. Calcdfor C₂₇H₂₆N₂O₂.0.23% H₂O.1.91% EtOAc.0.15% heptane: C, 78.36: H, 6.46:N, 6.67: found: C, 78.16: H, 6.47: N, 6.91.

Example 355

[1323]9-(4-Methoxy-2-methylphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indoledihydrochloride

[1324] A freshly prepared solution of sodium cyanoborohydride (0.10 g,1.6 mmol) in MeOH (0.50 mL) was added to a solution of9-(4-methoxy-2-methylphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(0.10 g, 0.33 mmol) in THF (3.0 mL) at 0° C. After 5 min, the ice bathwas removed. After 2 h, the reaction was diluted with H₂O, quenched with50% aqueous NaOH, and extracted with EtOAc (3×10 mL). The combinedorganic extracts were washed with brine, dried over Na₂SO₄, decanted,and concentrated. The crude product was purified by columnchromatography (Biotage, 40S) with CH₂Cl₂/MeOH/NH₄OH (976:21:3) to give72 mg of impure amine. The HCl salt was prepared to give 20 mg (16%) ofa tan solid: mp 225.5-228° C., IR (diffuse reflectance) 2954, 2849,2829, 2750, 2687, 2655, 2624, 2526, 2470, 1606, 1485, 1466, 1458, 1289,1240 cm⁻¹; MS (EI) m/z 308 (M⁺), 306, 278, 265, 264, 251, 250, 78, 63,56: Anal. Calcd for C₂₀H₂₄N₂O.2HCl: C, 62.99: H, 6.87: N, 7.35: found:C, 63.16: H, 7.00: N, 7.31.

Example 356

[1325] (5aS*,10bS*)-10-(2-chlorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1326] Prepared according to the procedure used to prepare10-(2,6-difluorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indolein 78% yield. ¹ H NMR (400 MHz, CD₃OD) δ1.37-1.65, 1.93-2.14, 2.45-2.88,3.17, 3.66, 4.21, 6.40-6.68, 7.07, 7.25-7.43, 7.50: MS (ESI+) forC₁₈H₁₈ClN₂ m/z 299.1 (M+H)⁺.

Example 357

[1327](5aS*,10bS*)-10-(2-methylphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1328] A 0° C. solution of10-(2-methylphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride (268 mg, 0.86 mmol) in trifluoroacetic acid (4 mL) wastreated with a solution of sodium cyanoborohydride (280 mg) in methanol(1 mL). The reaction was allowed to slowly warm to room temperature over3 hours then diluted with water and concentrated in vacuo to remove themajority of acid. The residue was made basic with 15% NaOH, extractedwith CH₂Cl₂ dried over MgSO₄ and concentrated in vacuo to give 184 mg ofa brown oil which was passed through a column of silica gel with 1:19methanol/chloroform with 1% NH₄OH to give 99 mg (41%) of a white foam asthe title compound: ¹H NMR (400 MHz, Acetone-d₆) δ7.28-7.20 (m, 4 H),6.97 (m, 1 H), 6.49 (m, 1H), 6.34 (m, 1 H), 5.01 (m, 1 H), 4.19-4.15 (m,1 H), 3.58 (m, 1H), 2.98 (m, 1 H), 2.61-2.55 (m, 2 H), 2.34-2.28 (m, 1H), 2.16 (s, 3 H), 2.10-1.85 (in, 2 H), 1.52-1.47 (m, 1 H), 1.25-1.15(m, 1 H); HRMS (FAB) calcd for C₁₉H₂₂N₂+H₁ 279.1861, found 279.1864.

Example 358

[1329](5aS*,10bS*)-10-(2-Methoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1330] A 0° C. solution of10-(2-methoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride from above (286 mg, 0.87 mmol) in trifluoroacetic acid (4mL) was treated with a solution of sodium cyanoborohydride (278 mg 4.42mmol) in methanol (1 mL). The reaction was allowed to slowly warm toroom temperature over 3.8 hours then diluted with water and concentratedin vacuo to remove the majority of acid. The residue was made basic with15% NaOH, extracted with CH₂Cl₂ dried over MgSO₄ and concentrated invacuo and passed through a column of silica gel with 1:19methanol/chloroform with 1% NH₄OH to give 91 mg (36%) of a white foam asthe title compound: ¹H NMR (400 MHz, Acetone-d₆) δ7.34-7.30 (m, 1 H),7.17 (dd, J=7.4 Hz, 1.7 Hz, 1 H), 7.06 (d, J=8.3 Hz, 1 H), 7.00-6.92 (m,2 H), 6.47 (d, J=7.7 Hz, 1 H), 6.42 (d, J=7.6 Hz, 1 H), 4.90 (br s, 1H), 4.19-4.14 (m, 1 H), 3.78 (s, 3 H), 3.65-3.60 (m, 1 H), 2.97-2.93 (m,1 H), 2.64-2.56 (m, 2 H) 2.35-2.29 (m, 1 H), 1.98-1.94 (m, 1 H),1.48-1.44 (m, 1 H), 1.28-1.23 (m, 1 H); HRMS (FAB) calcd forC₁₉H₂₂N₂O₁+H₁ 295.1810, found 295.1798.

Example 359

[1331](5aS*,10bS*)-10-(2-Propoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1332] A 0° C. solution of10-(2-propoxyphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (257 mg,0.80 mmol) in trifluoroacetic acid (4 mL) was treated with a solution ofsodium cyanoborohydride (269 mg 4.28 mmol) in methanol (2 mL). Thereaction was allowed to slowly warm to room temperature over 1.6 hoursthen diluted with water and concentrated in vacuo to remove the majorityof acid. The residue was made basic with 15% NaOH, extracted twice withCH₂Cl₂ dried over MgSO₄ and concentrated in vacuo and passed through acolumn of silica gel with 1:19 methanol/chloroform with 1% NH₄OH to give104 mg (40%) of a brown oil as the title compound: ¹H NMR (400 MHz,CDCl₃) δ7.32-7.30 (m, 1 H), 7.25 (dd, J=7.4 Hz, 1.7 Hz, 1 H), 7.11-7.07(m, 1 H), 7.02-6.96 (m, 2 H), 6.65-6.59 (m, 1 H), 4.24-4.21 (m, 1 H),3.97-3.84 (m, 2 H), 3.73 (dt, J=9.7 Hz, 3.3 Hz, 1 H), 3.13-3.08 (m, 1H), 2.80-2.76 (m, 1 H), 2.73-2.67 (m, 1 H), 2.47-2.41 (m, 1 H),2.06-2.04 (m, 1 H), 1.95-1.92 (m, 1 H), 1.75-1.70 (m, 2 H), 1.59-1.55(m, 1 H), 1.37-1.34 (m, 1 H) 0.95 (t, J=7.4 Hz, 3 H); HRMS (FAB) calcdfor C₂₁H₂₆N₂O+H₁: 323.2123 found 323.2116.

Examples 360 and 361

[1333](5aS,10bS)-10-(2-Propoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indoleand(5aR,10bR)-10-(2-Propoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1334] The racemic(5aS*,10bS*)-10-(2-propoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indolefrom above was resolved by chiral chromatography to give 0.010 g of abrown oil enriched in the more polar enantiomer (72% ee): ¹H NMR (400MHz, CDCl₃) δ7.34-7.30 (m, 1 H), 7.25 (dd, J=7.4 Hz, 1.7 Hz, 1 H),7.11-7.07 (m, 1 H), 7.02-6.96 (m, 2 H), 6.65-6.59 (m, 1 H), 4.27-4.21(m, 1 H), 3.98-3.89 (m, 2 H), 3.73 (dt, J=9.6 Hz, 3.4 Hz, 1 H),3.16-3.11 (m, 1 H), 2.80-2.71 (m, 2 H), 2.51-2.45 (m, 1 H), 2.08-2.05(m, 1 H), 1.98-1.93 (m, 1 H), 1.75-1.70 (m, 2 H), 1.59-1.55 (m, 1 H),1.40-1.38 (m, 1 H) 0.94 (t, J=7.4 Hz, 3 H); HRMS (FAB) calcd forC₂₁H₂₆N₂O+H₁: 323.2123, found 323.21 10. In addition 0.014 g of a brownoil as the less polar enantiomer was obtained: ¹H NMR (400 MHz, CDCl₃)δ7.34-7.30 (m, 1 H), 7.25 (dd, J=7.4 Hz, 1.7 Hz, 1 H), 7.11-7.07 (m, 1H), 7.02-6.96 (m, 2 H), 6.65-6.60 (m, 1 H), 4.27-4.21 (m, 1 H),3.96-3.89 (m, 2 H), 3.72 (dt, J=9.6 Hz, 3.4 Hz, 1 H), 3.15-3.10 (m, 1H), 2.81-2.69 (m, 2 H), 2.49-2.43 (m, 1 H), 2.08-2.04 (m, 1 H),1.98-1.92 (m, 1 H), 1.75-1.70 (m, 2 H), 1.59-1.55 (m, 1 H), 1.38-1.36(m, 1 H) 0.94 (t, J=7.4 Hz, 3 H); HRMS (FAB) calcd for C₂₁H₂₆N₂O+H₁:323.2123, found 323.2117.

[1335] Preparation 127

[1336] Preparation of (5aS*,10bS*)-tert-Butyl10-(2-fluorophenyl)-1,4,5,5a,6,10b-hexahydroazepino[4,5-b]indole-3(2H)-carboxylateand (5aS*,10bS*)-di(tert-butyl)10-(2-fluorophenyl)-1,2,4,5,5a,10b-hexahydroazepino[4,5-b]indole-3,6-dicarboxylate

[1337] A 0° C. solution of10-(2-fluorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (1.14 g,4.00 mmol) in trifluoroacetic acid (20 mL) was treated with a solutionof sodium cyanoborohydride (1.24 g 19.73 mmol) in methanol (5 mL). Thereaction was allowed to slowly warm to room temperature over 18.2 hoursthen diluted with water and concentrated in vacuo to remove the majorityof acid. The residue was made basic with 15% NaOH, extracted three timeswith CH₂Cl₂ dried over MgSO₄ and concentrated in vacuo to give a brownoil (0.86 g). The oil was dissolved in CH₂Cl₂ (25 mL) and treated withdi-tert-butyl dicarbonate (0.75 g, 3.44 mmol) and triethylamine (0.36 g,3.56 mmol). The reaction was stirred at room temperature for 3 hours.The reaction was concentrated in vacuo and the residue was dissolved inethyl acetate, washed successively with 2N HCl, saturated NaHCO₃, brine,dried over MgSO₄ and concentrated in vacuo to give a brown oil (1.0 g)which was passed through a column of silica gel with 20% ethylacetate/hexane to give (5aS*,10bS*)-di(tert-butyl)10-(2-fluorophenyl)-1,2,4,5,5a,10b-hexahydroazepino[4,5-b]indole-3,6-dicarboxylateas a white solid 0.32 g (22%): mp 166.0-169.3° C. ¹H NMR (400 MHz,CDCl₃) δ7.37-7.12 (m, δ1 H), 6.92 (d, J=7.6 Hz, 1 H), 4.67 (m, 1 H),4.11 (m, 1 H), 3.41 (m, 2 H), 3.15 (m, 2 H), 2.13 (m, 2 H), 1.62 (s, 9H), 1.42 (m, 11 H); MS m/z 483.5 (M⁺+H). A slower fraction from thecolumn gave (5aS*,10bS*)-tert-butyl10-(2-fluorophenyl)-1,4,5,5a,6,10b-hexahydroazepino[4,5-b]indole-3(2H)-carboxylateas a clear oil 0.41 g (35%): ¹H NMR (400 MHz, CDCl₃) δ7.37 (m, 2 H),7.23-7.16 (m, 3 H), 6.78-6.76 (m, 2 H), 4.31-4.26 (m, 1 H), 3.62-3.32(m, 4 H), 3.12 (m, 1 H), 2.09 (m, 2 H), 1.64 (m, 2 H), 1.43 (s, 9 H); MSm/z 383.4 (M⁺+H).

Example 362

[1338](5aS*,10bS*)-10-(2-Fluorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indoledihydrochloride

[1339] (5aS*,10bS*)-Di(tert-butyl)10-(2-fluorophenyl)-1,2,4,5,5a,10b-hexahydroazepino[4,5-b]indole-3,6-dicarboxylate(0.094 g, 0.19 mmol) was dissolved in a 4.0 N solution of HCl in dioxane(4 mL) and stirred at room temperature for 26.5 hours. After thereaction mixture was concentrated in vacuo CH₃OH was added and thesolution was concentrated in vacuo and recrystallized from CH₃OH/EtOActo give 0.054 g (72%) of a white solid as the title compound: mp248.0-256.7° C. ¹H NMR (400 MHz, DMSO-d₆) δ9.19 (m, 1 H), 9.05 (m, 1 H),7.51-7.43 (m, 2 H), 7.36-7.29 (m, 3 H), 7.03-6.98 (m, 2 H) 4.34-4.33 (m,1 H), 3.85 (m, 1 H), 3.29 (m, 1 H), 3.06 (m, 1 H), 2.90 (m, 1 H),2.69-2.67 (m, 1 H), 2.27 (m, 2 H), 1.67 (m, 1 H), 1.36-1.34 (m, 1 H);¹³C NMR (100 MHz, DMSO-d₆) δ159.8, 157.3, 132.7, 130.8, 130.7, 130.2,130.1, 128.6, 126.4, 126.2, 124.8, 124.7, 115.9, 115.7, 59.7, 44.8,43.9, 41.7, 26.5, 25.7: IR (diffuse reflectance) 2954 (s), 2847 (s),2817 (s,b), 2755 (s), 2726 (s,b), 2668 (s,b), 2651 (s,b), 2572 (s,b),2538 (s), 2469 (s), 2350, 2342, 1738, 1474, 771 cm⁻¹; HRMS (FAB) calcdfor C₁₈H₁₉FN₂+H₁: 283.1610 found 283.1612.

Examples 363 and 364

[1340](5aS,10bS)-10-(2-Fluorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indoledihydrochloride and(5aR,10bR)-10-(2-Fluorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indoledihydrochloride

[1341] The racemic (5aS*,10bS*)-tert-butyl10-(2-fluorophenyl)-1,4,5,5a,6,10b-hexahydroazepino[4,5-b]indole-3(2H)-carboxylatefrom above was resolved by chiral chromatography to give a clear oil(0.149 g) as the more polar enantiomer. This was dissolved in a 4.0 Nsolution of HCl in dioxane (5 mL) and stirred at room temperature for 5hours. After the reaction mixture was concentrated in vacuo CH₃OH wasadded and the solution was concentrated in vacuo and recrystallized fromCH₃OH/EtOAc to give 0.045 g (33%) of a white solid as the titlecompound: mp 246.5-250.0C. ¹H NMR (400 MHz, DMSO-d₆) δ9.12 (m, 1 H),9.01 (m, 1 H), 7.50-7.42 (m, 2 H), 7.36-7.29 (m, 3 H), 6.97 (m, 2 H),4.32-4.31 (m, 1 H), 3.82 (m, 1 H), 3.26 (m, 1 H), 3.06 (m, 1 H), 2.87(m, 1 H), 2.70 (m, 1 H), 2.24 (m, 2 H), 1.65 (m, 1 H), 1.37 (m, 1 H);¹³C NMR (100 MHz, DMSO-d₆) δ159.8, 157.3, 132.6, 130.8, 130.7, 130.1,128.5, 126.5, 126.4, 124.7, 124.7, 115.9, 115.7, 59.7, 44.7, 43.8, 41.7,26.7, 25.7: ¹⁹F NMR (376 MHz, DMSO-d₆) δ−116.1 (m); IR (diffusereflectance) 2954, 2844 (s), 2794 (s), 2750 (s), 2680 (s), 2665 (s),2651 (s), 2624 (s,b), 2578, 2547 (b), 2537, 2524, 2494 (s), 2468 (s),763 cm⁻¹. HRMS (FAB) calcd for C₁₈H₁₉FN₂+H₁: 283.1610 found 283.1603. Inaddition a clear oil (0.185 g) was obtained as the less polarenantiomer. This was dissolved in a 4.0 N solution of HCl in dioxane (5mL) and stirred at room temperature for 5 hours. After the reactionmixture was concentrated in vacuo CH₃OH was added and the solution wasconcentrated in vacuo and recrystallized from CH₃OH/EtOAc to give 0.127g (74%) of a white solid as the title compound: mp 247.6-250.0° C.; ¹HNMR (400 MHz, DMSO-d₆) δ9.17 (m, 1 H), 9.03 (m, 1 H), 7.51-7.43 (m, 2H), 7.36-7.29 (m, 3 H), 7.01-6.96 (m, 2 H), 4.34-4.33 (m, 1 H), 3.84 (m,1 H), 3.29 (m, 1 H), 3.06 (m, 1 H), 2.89 (m, 1 H), 2.69-2.67 (m, 1 H),2.26 (m, 2 H), 1.67 (m, 1 H), 1.36-1.34 (m, 1 H); ¹³C NMR (100 MHz,DMSO-d₆) δ159.8, 157.3, 132.7, 130.8, 130.7, 130.2, 130.1, 128.6, 126.4,126.3, 124.7, 124.7, 115.9, 115.7, 59.7, 44.8, 43.8, 41.7, 26.6, 25.7:¹⁹F NMR (376 MHz, DMSO-d₆) δ−116.1 (m); IR (diffuse reflectance) 2844,2834 (b), 2814 (b), 2793 (s), 2751 (s), 2729 (s,b), 2680 (s), 2665 (s),2651 (s), 2624 (s,b), 2578, 2548, 2494 (s), 2468 (s), 763 (s) cm⁻¹; HRMS(FAB) calcd for C₁₈H₁₉FN₂+H₁: 283.1610 found 283.1607.

Example 365

[1342](5aR*,10bS*)-10-(2-Fluorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1343] A solution of10-(2-fluorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.49 g,1.74 mmol) in THF (6 mL) was added dropwise to 1.5 M borane-THF complex(6 mL, 9 mmol) and stirred at room temperature for 1.25 hours. Theexcess borane was quenched with H₂O and the mixture was added to TFA at0° C. After 0.3 hours the reaction was diluted with H₂O and concentratedin vacuo. The residue was diluted with H₂O, made basic with 15% NaOH andextracted three times with CH₂Cl₂. The extracts were dried over MgSO₄and concentrated in vacuo to give a white solid which was passed througha column of silica gel with 1:19 acetone/CHCl₃ with 1% NH₄OH to give0.25 g (51%) of a light brown solid as the title compound: ¹H NMR (400MHz, CDCl₃) δ7.38-7.33 (m, 2 H), 7.21-7.10 (m, 3 H), 6.69 (d, J=7.7 Hz,2 H), 3.89 (dt, J=11.0 Hz, 3.5 Hz, 1 H), 3.60-3.53 (m, 1 H), 3.18-3.12(m, 1 H), 2.94-2.88 (m, 1 H), 2.83 (m, 1 H), 2.74-2.72 (m, 1 H),2.21-2.16 (m, 1 H), 1.97-1.87 (m, 1 H), 1.67 (m, 1 H), 1.26 (m, 1 H); MSm/z 283.2 (M⁺+H).

Examples 366 and 367

[1344](5aR,10bS)-10-(2-Fluorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indoleand(5aS,10bR)-10-(2-fluorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1345] The racemic trans-10-(2-fluorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole from above was resolved by chiralchromatography to, give 0.104 g of a brown oil as the more polarenantiomer: ¹H NMR (400 MHz, DMSO-d₆) δ7.41-7.37 (m, 1 H), 7.31 (m, 1H), 7.25-7.21 (m, 2 H), 6.98-6.94 (m, 1 H), 6.49 (d, J=7.7 Hz, 1 H),6.41 (d, J=7.5 Hz, 1 H), 3.65 (m, 1 H), 3.31 (m, 1 H), 2.96-2.92 (m, 1H), 2.68 (m, 1 H), 2.63-2.56 (m, 2 H), 2.02-1.98 (m, 1 H), 1.64 (m, 1H), 1.41 (m, 1 H), 1.00 (m, 1 H); HRMS (FAB) calcd for C₁₈H₁₉F₁N₂+H₁:283.1610 found 283.1620. In addition 0.099 g of a brown oil as the lesspolar enantiomer was obtained: ¹H NMR (400 MHz, CDCl₃) δ7.35-7.32 (m, 2H), 7.19-7.09 (m, 3 H), 6.68 (d, J=7.6 Hz, 2 H), 3.89-3.83 (m, 1 H),3.59-3.52 (m, 1 H), 3.16-3.10 (m, 1 H), 2.92-2.86 (m, 1 H), 2.80 (m, 1H), 2.71-2.69 (m, 1 H), 2.19-2.15 (m, 1 H), 1.95-1.85 (m, 1 H), 1.67 (m,1 H), 1.24 (m, 1 H); IR (diffuse reflectance) 3247, 2938, 2846, 2752(b), 1591, 1500, 1472, 1439, 1262, 1247, 1214, 819, 789, 758 (s), 737cm⁻¹. HRMS (FAB) calcd for C₁₈H₁₉F₁N₂+H₁: 283.1610 found 283.1623.

Example 368

[1346](5aR*,10bS*)-10-(2,4-dichlorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indolemaleic acid salt

[1347] Prepared according to the procedure used to prepare(5aS*,10bS*)-10-(2-methoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole,the title compound was obtained: MS (ESI+) m/z 333.2 (MH⁺).

Example 369

[1348](5aR*,10bS*)-10-(4-methoxy-2-methylphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indolemaleic acid salt

[1349] Prepared according to the procedure used to prepare(5aS*,10bS*)-10-(2-methoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole,the title compound was obtained: mp 142-146° C.; IR (diffusereflectance) 3022, 3002, 2957, 2833, 1607, 1586, 1533, 1508, 1469, 1453,1380, 1366, 1291, 1237, 864 cm⁻¹; MS (EI) m/z 308 (M+), 264, 263, 252,251, 250, 236, 84, 56, 54: HRMS (FAB) calcd for C₂₀H₂₄N₂O+H 309.1967,found 309.1958.

Example 370

[1350](5aR*,10bS*)-10-(2-ethoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1351] Prepared according to the procedure used to prepare(5aS*,10bS*)-10-(2-methoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole,the title compound was obtained: 0.14 g (66%), IR (mull) 3023, 1597,1590, 1578, 1500, 1442, 1414, 1272, 1250, 1233, 1127, 1046, 787, 754,745 cm⁻¹; MS (EI) m/z 308 (M+), 264, 252, 251, 250, 236, 234, 222, 220,56: HRMS (FAB) calcd for C₂₀H₂₄N₂O+H 309.1967, found 309.1950.

Examples 371 and 372

[1352] (5aS,10bS)-10-(2-ethoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indoleand (5aR,10bR)-10-(2-ethoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1353] The racemic(5aR*,10bS*)-10-(2-ethoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indolewas purified by chiral chromatography (elution with 2-6%MeOH/chloroform+1% ammonium hydroxide) to give 0.038 g of a clear oilwhich was filtered through a fine fritted funnel to give 0.029 g of abeige foam: MS (EI) m/z 309 (MH+); HPLC retention time 100% 3.24 min. Inaddition, 0.025 g of a clear oil was obtained: MS (EI) m/z 309 (MH+);HPLC retention time 100% 3.29 min.

Example 373

[1354] (5aR*,10bS*)-10-phenyl-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole maleic acid salt

[1355] Prepared according to the procedure used to prepare(5aS*,10bS*)-10-(2-methoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole,the title compound was obtained: 45 mg (42%); IR (diffuse reflectance)3053, 3028, 1645, 1638, 1588, 1569, 1550, 1532, 1499, 1474, 1457, 1366,865, 762, 704 cm⁻¹; MS (EI) m/z 264 (M+), 264, 220, 219, 218, 208, 207,206, 204, 193, 165: HRMS (FAB) calcd for C₁₈H₂₀N₂+H 265.1704, found265.1697: Anal. Calcd for C₁₈H₂₀N₂.C₄H₄O₄: C, 69.46: H, 6.36: N, 7.36,found: C, 69.29: H, 6.31: N, 7.34

Example 374

[1356](5aS*,10bS*)-10-(3,5-difluorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1357] In a 50 mL 2-neck round-bottomed flask10-(3,5-difluorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride was dissolved in TFA (3 mL) and cooled to 0° C. A solutionof sodium cyanoborohydride (0.084 g, 1.34 mmol) in MeOH was added andthe mixture was stirred at room temperature for 2 h. Water was added,followed by 15% NaOH until the pH of the mixture was basic, and themixture was extracted with EtOAc. The organic layer was concentrated togive 0.21 g of a brown oil. Column chromatography (elution with 2-6%MeOH/chloroform) gave 0.060 g (74%) of the title product as a clear oil:MS (EI) m/z 300 (M+), 300, 256, 255, 244, 243, 242, 240, 229, 201, 56:HRMS (FAB) calcd for C₁₈H₁₈F₂N₂+H₁ 301.1516, found 301.1500.

Example 375

[1358](5aS*,10bS*)-10-(2-Butoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1359] Following the procedure for(5aS*,10bS*)-10-(2-propoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole,making non-critical variations, the title compound was obtained as 76 mg(61%) of a brown oil: ¹H NMR (400 MHz, CDCl₃) δ7.34-7.30 (m, 1 H), 7.25(dd, J=7.4 Hz, 1.6 Hz, 1 H), 7.11-7.07 (m, 1 H), 7.03-6.97 (m, 2 H),6.65 (d, J=7.5, 1 H), 6.61 (d, J=7.7 Hz, 1 H), 4.26-4.20 (m, 1 H),4.01-3.92 (m, 2 H), 3.75-3.70 (m, 1 H), 3.14-3.09 (m, 1 H), 2.79-2.76(m, 1 H), 2.72-2.67 (m, 1 H), 2.47-2.44 (m, 1 H), 2.07-2.04 (m, 1 H),1.97-1.89 (m, 1 H), 1.71-1.66 (m, 2 H), 1.59-1.56 (m, 1 H), 1.43-1.31(m, 3 H), 0.92 (t, J=7.4 Hz, 3 H); HRMS (FAB) calcd for C₂₂H₂₈N₂O+H₁:337.2280 found 337.2274.

Example 376 and 377

[1360](5aS,10bS)-10-(2-Butoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indoleand(5aR,10bR)-10-(2-Butoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1361] The racemic(5aS*,10bS*)-10-(2-butoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indolefrom above was resolved by chiral chromatography to give 0.020 g of aclear oil as the more polar enantiomer: ¹H NMR (400 MHz, CDCl₃)δ7.34-7.30 (m, 1 H), 7.24 (dd, J=7.4 Hz, 1.7 Hz, 1 H), 7.11-7.07 (m, 1H), 7.02-6.96 (m, 2 H), 6.65 (d, J=7.5, 1 H), 6.61 (d, J=7.7 Hz, 1 H),4.25-4.20 (m, 1 H), 4.01-3.92 (m, 2 H), 3.72 (dt, J=9.7 Hz, 3.2 Hz, 1H), 3.15-3.09 (m, 1 H), 2.81-2.76 (m, 1 H), 2.73-2.68 (m, 1 H),2.47-2.44 (m, 1 H), 2.09-2.05 (m, 1 H), 1.98-1.92 (m, 1 H), 1.71-1.65(m, 2 H), 1.59-1.55 (m, 1 H), 1.42-1.35 (m, 3 H), 0.92 (t, J=7.4 Hz, 3H); HRMS (FAB) calcd for C₂₂H₂₈N₂O+H₁: 337.2280 found 337.2293.

[1362] In addition a clear oil (0.019 g) was obtained as the less polarenantiomer: ¹H NMR (400 MHz, CDCl₃) δ7.34-7.30 (m, 1 H), 7.24 (dd, J=7.4Hz, 1.7 Hz, 1 H), 7.11-7.07 (m, 1 H), 7.02-6.96 (m, 2 H), 6.65 (d,J=7.5, 1 H), 6.61 (d, J=7.7 Hz, 1 H), 4.25-4.20 (m, 1 H), 4.01-3.92 (m,2 H), 3.72 (dt, J=9.7 Hz, 3.2 Hz, 1 H), 3.15-3.09 (m, 1 H), 2.81-2.76(m, 1 H), 2.73-2.68 (m, 1 H), 2.47-2.44 (m, 1 H), 2.09-2.05 (m, 1 H),1.98-1.92 (m, 1 H), 1.71-1.65 (m, 2 H), 1.59-1.55 (m, 1 H), 1.42-1.35(m, 3 H), 0.92 (t, J=7.4 Hz, 3 H); HRMS (FAB) calcd for C₂₂H₂₈N₂O+H₁:337.2280 found 337.2279.

Example 378

[1363](5aS*,10bS*)-10-[2-(Cyclopropylmethoxy)phenyl]-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1364] Following the procedure for the preparation of(5aS*,10bS*)-10-(2-propoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole,making non-critical variations, the title compound was obtained as 17 mg(23%) of a brown oil: ¹H NMR (400 MHz, CDCl₃) δ7.33-7.26 (m, 2 H),7.13-7.09 (m, 1 H), 7.04-6.95 (m, 2 H), 6.80-6.61 (m, 2 H), 4.29-4.23(m, 2 H), 3.86-3.78 (m, 3 H), 3.15-3.09 (m, 1 H), 2.82-2.77 (m, 1 H),2.73-2.68 (m, 1 H), 2.47-2.42 (m, 1 H), 2.12-2.05 (m, 1 H), 1.98-1.92(m, 1 H), 1.60-1.56 (m, 1 H), 1.37-1.34 (m, 1 H), 1.23-1.19 (m, 1 H),0.58-0.55 (m, 2 H), 0.28-0.25 (m, 2 H); HRMS (FAB) calcd forC₂₂H₂₆N₂O+H₁: 335.2123 found 335.2115.

Example 379

[1365](5aS*,10bS*)-10-[2-(Pentyloxy)phenyl]-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1366] Following the procedure for the preparation of(5aS*,10bS*)-10-(2-propoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole,making non-critical variations, the title compound was obtained as 144mg (42%) of a brown oil: ¹H NMR (400 MHz, CDCl₃) δ7.34-7.24 (m, 2 H),7.11-7.07 (m, 1 H), 7.02-6.91 (m, 2 H), 6.65 (d, J=7.5 Hz, 1 H), 6.61(d, J=7.7 Hz, 1 H), 4.26-4.21 (m, 1 H), 4.00-3.90 (m, 2 H), 3.72 (dt,J=9.6 Hz, 3.1 Hz, 1 H), 3.14-3.09 (m, 1 H), 2.81-2.76 (m, 1 H),2.73-2.68 (m, 1 H), 2.48-2.42 (m, 1 H), 2.09-2.04 (m, 1 H), 1.97-1.92(m, 1 H), 1.73-1.68 (m, 2 H), ), 1.59-1.56 (m, 1 H), 1.35-1.33 (m, 5 H),0.90 (t, J=6.9 Hz, 3 H); HRMS (FAB) calcd for C₂₃H₃₀N₂O+H₁: 351.2436found 351.2428.

Example 380

[1367](5aS*,10bS*)-10-[2-(Hexyloxy)phenyl]-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1368] Following the procedure for the preparation of(5aS*,10bS*)-10-(2-propoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole,making non-critical variations, the title compound was obtained as 136mg (41%) of a brown oil: ¹H NMR (400 MHz, CDCl₃) δ7.34-7.30 (m, 2 H),7.27-7.25 (m, 1 H), 7.10-7.07 (m, 1 H), 7.02-6.96 (m, 2 H), 6.65 (d,J=7.5 Hz, 1 H), 6.61 (d, J=7.7 Hz, 1 H), 4.25-4.21 (m, 1 H), 4.00-3.90(m, 2 H), 3.73 (dt, J=9.6 Hz, 3.1 Hz, 1 H), 3.14-3.10 (m, 1 H),2.81-2.68 (m, 2 H), 2.49-2.43 (m, 1 H), 2.09-2.04 (m, 1 H), 1.98-1.92(m, 1 H), 1.72-1.66 (m, 2 H), ), 1.59-1.55 (m, 1 H), 1.37-1.30 (m, 7 H),0.90 (t, J=6.8 Hz, 3 H); HRMS (FAB) calcd for C₂₄H₃₂N₂O+H₁: 365.2592found 365.2585.

Example 381

[1369](5aS*,10bS*)-10-(2-Isopropoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1370] Following the procedure for the preparation of(5aS*,10bS*)-10-(2-propoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indolemaking non-critical variations, the title compound was obtained as 124mg (59%) of a brown oil: ¹H NMR (400 MHz, CDCl₃) δ7.32-7.26 (m, 2 H),7.10-7.07 (m, 1 H), 7.04-6.97 (m, 2 H), 6.65 (d, J=7.5 Hz, 1 H), 6.61(d, J=7.7 Hz, 1 H), 4.38-4.33 (m, 1 H), 4.27-4.21 (m, 1 H), 3.80 (dt,J=9.6 Hz, 3.3 Hz, 1 H), 3.14-3.08 (m, 1 H), 2.80-2.69 (m, 2 H),2.49-2.44 (m, 1 H), 2.10-2.04 (m, 1 H), 1.97-1.92 (m,1 H), 1.58-1.52 (m,1 H), 1.39-1.32 (m, 1 H), 1.28 (d, J=6.1 Hz, 3 H), 1.15 (d, J=6.8 Hz, 3H); HRMS (FAB) calcd for C₂₁H₂₆N₂O+H₁: 323.2123 found 323.2136.

Example 382

[1371](5aS*,10bS*)-10-[2-(cyclopentloxy)phenyl]-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1372] Following the procedure for the preparation of(5aS*,10bS*)-10-(2-propoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole,making non-critical variations, the title compound was obtained as 255mg (64%) of a brown oil: ¹H NMR (400 MHz, CDCl₃) δ7.35-7.23 (m, 2 H),7.10-7.06 (m, 1 H), 7.03-6.89 (m, 2 H), 6.63-6.59 (m, 2 H), 4.75-4.70(m, 1 H), 4.26-4.20 (m, 1 H), 3.76-3.70 (m, 1 H), 3.18-3.13 (m, 1 H),2.79-2.72 (m, 2 H), 2.52-2.47 (m, 1 H), 2.11-2.08 (m, 1 H), 1.96-1.87(m, 3 H), 1.75-1.69 (m, 3 H), 1.66-1.53 (m, 4 H), 1.39-1.30 (m, 1 H);HRMS (FAB) calcd for C₂₃H₂₈N₂O+H₁: 349.2280 found 349.2286.

Example 383

[1373](5aS*,10bS*)-10-[2-(Cyclohexyloxy)phenyl]-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1374] Following the procedure for the preparation of(5aS*,10bS*)-10-(2-propoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole,making non-critical variations, the title compound was obtained as 125mg (51%) of a clear oil: ¹H NMR (400 MHz, CDCl₃) δ7.30-7.27 (m, 2 H),7.10-7.06 (m, 1 H), 7.02-6.97 (m, 2 H), 6.66 (d, J=7.6 Hz, 1 H), 6.61(d, J 7.7 Hz, 1 H), 4.26-4.20 (m, 1 H), 4.19-4.09 (m, 1 H), 3.13-3.08(m, 1 H), 2.81-2.76 (m, 1 H), 2.73-2.68 (m, 1 H), 2.49-2.43 (m, 1 H),2.06-2.03 (m, 1 H), 1.97-1.89 (m, 2 H), 1.72 (m, 2 H), 1.59-1.48 (m, 3H), 1.36-1.19 (m, 5 H); HRMS (FAB) calcd for C₂₄H₃₀N₂O+H₁: 363.2436found 363.2421.

Example 384

[1375](5aS*,10bS*)-10-[2-(Cyclobutyloxy)phenyl]-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1376] Following the procedure for the preparation of(5aS*,10bS*)-10-(2-propoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole,making non-critical variations, the title compound was obtained as 85 mg(48%) of a white solid: ¹H NMR (400 MHz, CDCl₃) δ7.30-7.26 (m, 2 H),7.12-7.08 (m, 1 H), 7.02-6.98 (m, 1 H), 6.91-6.80 (m, 1 H), 6.65-6.60(m, 1 H), 4.68-4.61 (m, 1 H), 4.28-4.22 (m, 1 H), 3.83-3.78 (m, 1 H),3.14-3.08 (m, 1 H), 2.81-2.78 (m, 1 H), 2.73-2.68 (m, 1 H), 2.49-2.38(m, 3 H), 2.17-2.03 (m, 2 H), 1.98-1.83 (m, 3 H), 1.70-1.57 (m, 2 H),1.38-1.37 (m, 1 H); HRMS (FAB) calcd for C₂₂H₂₆N₂O+H₁: 335.2123 found335.2121.

Example 385

[1377] (5aS*,10bS*)-10-(2,6-difluorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1378] NaCNBH₃ (0.223 g, 3.54 mmol) was added to a solution of10-(2,6-difluorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (0.336g, 1.13 mmol) in CF₃CO₂H (6 mL), which was cooled in an ice-water bath.After stirring for 4 h, the reaction mixture was quenched by adding 6NHCl (6 mL). The resulting mixture was refluxed for 0.45 h. The mixturewas cooled and made basic by the addition of 6N NaOH (25 mL). The basicmixture was combined with CHCl₃ (30 mL) and H₂O (5 mL) and the layerswere separated. The aqueous layer was extracted with CHCl₃ (2×50 mL).The combined organic layers were dried over Na₂SO₄, filtered andconcentrated. The crude product (0.78 g) was chromatographed (SiO₂ 35 g,eluted with 90:10:2 CH₂Cl₂:CH₃OH:conc. NH₄OH) to yield10-(2,6-difluorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole(0.232 g) in 69% yield. ¹H NMR (400 MHz, CD₃OD) δ1.37, 1.61, 1.94, 2.05,2.44, 2.65-2.73, 3.05, 3.54, 4.19, 6.52, 6.63, 7.03-7.09, 7.41: MS(ESI+) for C₁₈H₁₈F₂N₂ m/z 301.2 (M+H)⁺.

Example 386

[1379] (5aS*,10bS*)-10-[2-(trifluoromethoxy)phenyl]-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1380] Prepared according to the procedure used to prepare10-(2,6-difluorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indolein 88% yield. ¹H NMR (400 MHz, CD₃OD) δ1.30, 1.52, 1.94, 2.06, 2.40,2.65, 2.68, 3.07, 3.67, 4.19, 6.53, 6.62, 7.06, 7.38-7.49: MS (ESI+) forC₁₉H₁₉F₃N₂O m/z 349.1 (M+H)⁺.

Example 387

[1381] (5aS*,10bS*)-10-[2-(trifluoromethyl)phenyl]-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1382] Prepared according to the procedure used to prepare10-(2,6-difluorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indolein 67% yield. ¹H NMR (400 MHz, CD₃OD) δ1.25, 1.37, 1.53, 1.63,1.90-2.07, 2.37, 2.59-2.74, 3.07, 3.14, 3.35, 3.64, 4.10, 4.21, 6.43,6.51, 6.61, 6.62, 7.01, 7.02, 7.33, 7.44, 7.54, 7.64, 7.79: MS (ESI+)for C₁₉H₁₉F₃N₂ m/z 333.2 (M+H)⁺.

Example 388

[1383](5aS*,10bS*)-10-(4-Chlorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indoledihydrochloride

[1384] 10-(4-Chlorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolehydrochloride (140mg) was dissolved in TFA (3 ml), cool to 0° C. andsodium cyanoborohydride was added portionwise (150 mg). The reactionmixture stirred two hours, was quenched with 2N NaOH, extracted withEtOAc, dried over MgSO₄, filtered and concentrated. The product wasdissolved in EtOAc and 1N HCl in Et₂O was added. The solvent wasevaporated and solid recrystallized from EtOAc/MeOH to provide the titlecompound: ¹H NMR (DMSO-d₆) δ1.31, 1.66, 2.21, 2.7, 2.91, 3.03, 3.27,4.1-4.4, 6.88, 7.25, 7.52. HRMS (FAB) calcd for C₁₈H₂₁ClN₂ (MH⁺)299.1315, found 299.1321.

Example 389

[1385](5aS*,10bS*)-10-(3-chlorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indoledihydrochloride

[1386] Following the procedure for the preparation of10-(4-chlorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indoledihydrochloride, making non-critical variations, starting from10-(3-chlorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indoledihydrochloride the title compound was prepared: ¹H NMR (DMSO-d₆) δ1.35,1.55, 2.10, 2.71, 3.05, 3.28, 3.97, 4.20, 6.65, 7.12, 7.4-7.5, 8.8. HRMS(FAB) calcd for C₁₈H₂₁ClN₂ (MH⁺) 299.1315, found 299.1306.

Example 390

[1387](5aS*,10bS*)-10-(2,4-dichlorophenyl)-6-(2-phenoxyethyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1388] Following the procedure for the preparation of10-(4-chlorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indoledihydrochloride, making non-critical variations, starting from10-(2,4-dichlorophenyl)-6-(2-phenoxyethyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolethe title compound was prepared: ¹H NMR (CD₃OD) δ1.47, 1.55, 2.20, 2.66,2.90, 3.19, 3.52-3.63, 4.13-4.21, 6.44, 6.50, 6.93, 7.15, 7.25-7.42,7.57. HRMS (FAB) calcd for C₂₆H₂₆Cl₂N₂O₂ (MH⁺) 453.1500, found 453.1520.

[1389] Preparation 128

[1390] Preparation of di(tert-butyl)10-(2,4-dichlorophenyl)-1,2,4,5,5a,10b-hexahydroazepino[4,5-b]indole-3,6-dicarboxylate

[1391] To a solution of 1-tert-butyl10-(2,4-dichlorophenyl)-1,4,5,5a,6,10b-hexahydroazepino[4,5-b]indole-3(2H)-carboxylate(300 mg) in dioxane (2.30 ml) was added diisopropylethylamine (0.24 ml)and Boc₂O (755 mg). The reaction mixture was heated at 100° C. for 16 h,poured into brine, extracted with CH₂Cl₂, dried over MgSO₄, filtered andconcentrated. Purification via flash chromatography (silica gel,EtOAc/Hexanes 1:15) provided the title compound: ¹H NMR (CDCl₃) δ1.41,1.42, 1.47, 5.07, 3.04-3.19, 3.38, 3.85, 4.00, 4.62, 6.73, 6.85, 7.13,7.22-7.45, 7.45, 7.54, 7.74. HRMS (FAB) calcd for C₂₈H₃₄Cl₂N₂O₄ (MH⁺)533.1974, found 533.1978.

[1392] Preparation 129

[1393] Preparation of 1-di(tert-butyl)9-chloro-10-(2,4-dichlorophenyl)-1,2,4,5,5a,10b-hexahydroazepino[4,5-b]indole-3,6-dicarboxylate

[1394] To a solution of di(tert-butyl)10-(2,4-dichlorophenyl)-1,2,4,5,5a,10b-hexahydroazepino[4,5-b]indole-3,6-dicarboxylate(388 mg) in DMF (7.1 ml)was added N-chlorosuccinimide (95 mg). Thereaction mixture stirred 48 h, was poured into H₂O, extracted with Et₂O,dried over MgSO₄, filtered and concentrated. Purification via flashchromatography (silica gel, EtOAc:hexanes, 1:15) provided the titlecompound. ¹H NMR (CDCl₃) δ1.46, 2.09, 3.11, 3.25, 3.39, 3.52, 3.67,4.57, 7.07, 7.24, 7.54, 7.71. HRMS (FAB) calcd for C₂₈H₃₃Cl₃N₂O₄ (MH⁺)567.1584, found 567.1566

Example 391

[1395](5aS*,10bS*)-9-chloro-10-(2,4-dichlorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1396] To a solution of 1-di(tert-butyl)9-chloro-10-(2,4-dichlorophenyl)-1,2,4,5,5a,10b-hexahydroazepino[4,5-b]indole-3,6-dicarboxylate(145 mg) in CH₂Cl₂ (5 ml) was added TFA (1 ml). The reaction mixture wasstirred 1 h, quenched with 2N NaOH, extracted with CH₂Cl₂, dried overMgSO₄, filtered and concentrated. Purification via flash chromatography(silica gel, CH₂Cl₂:MeOH, 9:1 with 0.5% NH₄OH) provided the titlecompound: ¹H NMR (CD₃OD) δ1.31, 1.43, 2.05, 2.67, 2.88, 3.24, 3.46,4.25, 6.60, 7.11, 7.28, 7.45, 7.59. HRMS (FAB) calcd for C₁₈H₁₇Cl₃N₂(MH⁺) 367.0535, found 367.0525.

Example 392

[1397](5aS*,10bS*)-10-[3-(2-chlorophenoxy)propyl]-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1398] Following the procedure for the preparation of10-(4-chlorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indoledihydrochloride, making non-critical variations, starting from10-[3-(2-chlorophenoxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolethe title compound was prepared: ¹H NMR (CDCl₃) δ1.99-2.20, 2.27, 2.78,2.93-3.05, 3.51, 4.11, 6.48, 6.62, 6.92, 7.03, 7.19, 7.38, 7.40. HRMS(FAB) calcd for C₂₁H₂₅ClN₂O₁ (MH⁺) 357.1733, found 357.1749.

Example 393

[1399](5aS*,10bS*)-10-(2-phenylethyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1400] Following the procedure for the preparation of10-(4-chlorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indoledihydrochloride, making non-critical variations, starting from10-(2-phenylethyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole the titlecompound was prepared: ¹H NMR (CDCl₃) δ2.02, 2.14, 2.31, 2.79, 2.88,2.97, 3.15, 3.64, 4.18, 6.52, 6.70, 7.07, 7.16, 7.21, 7.27, 9.5-9.7.HRMS (FAB) calcd for C₂₀H₂₄N₂ (MH⁺) 293.2018, found 293.2013.

Example 394

[1401](5aS*,10bS*)-10-[3-(2-naphthyloxy)propyl]-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1402] Following the procedure for the preparation of10-(4-chlorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indoledihydrochloride, making non-critical variations, starting from10-[3-(2-naphthyloxy)propyl]-1,2,3,4,5,6-hexahydroazepino[4,5-b]indolethe title compound was prepared: ¹H NMR (CDCl₃) δ1.89-2.08, 2.22, 2.77,2.91, 3.07, 3.26, 3.51, 3.67, 4.14, 6.47, 6.64, 7.05, 7.12, 7.16, 7.19,7.35, 7.45, 7.47, 7.78. HRMS (FAB) calcd for C₂₅H₂₈N₂O (MH⁺) 373.2280,found 373.2288.

Example 395

[1403](5aS*,10bS*)-10-(3-phenoxypropyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1404] Following the procedure for the preparation of10-(4-chlorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indoledihydrochloride, making non-critical variations, starting from10-(3-phenoxypropyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole the titlecompound was prepared: ¹H NMR (CDCl₃) δ2.02-2.14, 2.27, 2.74, 2.90-3.03,3.45, 3.50, 3.98, 4.14, 4.50, 6.47, 6.63, 6.91, 6.95, 7.03, 7.30. HRMS(FAB) calcd for C₂₁H₂₆N₂O (MH⁺) 323.2123, found 323.2104.

Example 396

[1405](5aS*,10bS*)-N-(2-chlorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indol-10-amine

[1406] Following the procedure for the preparation of(5aS*,10bS*)-10-(4-chlorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indoledihydrochloride, making non-critical variations, starting fromN-(2-chlorophenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indol-10-amine thetitle compound was prepared: ¹H NMR (DMSO-d₆) δ1.68, 1.77, 1.93, 2.58,2.73, 2.95, 5.62, 6.20, 6.77-6.82, 6.86, 6.94, 7.14, 7.37. HRMS (FAB)calcd for C₁₈H₂₀ClN₃ (MH⁺) 314.1424, found 314.1422.

[1407] Preparation 130

[1408] Preparation of 10-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole

[1409] Following the procedure of9-(4-methoxy-2-methylphenyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole,making non-critical variations, the title compound was obtained. MS (EI)m/z 265.0 (MH⁺).

Example 397

[1410](5aS*,10bS*)-10-Bromo-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1411] Following the procedure of(5aS*,10bS*)-9-(4-Methoxy-2-methylphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indoledihydrochloride, making non-critical variations, the title compound wasobtained. ¹H NMR (400 MHz, CDCl₃) δ6.87 (m, 1H), 6.80 (d, J=7.9 Hz, 1H),6.47 (d, J=7.7 Hz, 1H), 4.23 (m, 1H), 3.92 (bs, 1H), 3.50 (m, 1H), 3.21(m,1H), 3.08 (dt, J=13.5, 4.4 Hz, 1H), 2.86 (m, 1H), 2.78 (dd, J=13.5,8.9 Hz, 1H), 2.21 (m, 1H), 2.07 (m, 2H), 1.97 (m, 1H); IR (diffusereflectance) 2926, 2908, 2852, 1602, 1574, 1451, 1370, 1291, 1282, 1260,1139, 906, 832, 772, 718 cm⁻¹; MS (EI) m/z 268, 266 (M+), 224, 222, 212,185, 144, 143, 129, 128: HRMS (FAB) calcd for C₁₂H₁₅BrN₂+H 267.0497,found 267.0496.

[1412] Preparation 131

[1413] Preparation of (5aS*,10bS*)-tert-butyl10-bromo-1,4,5,5a,6,10b-hexahydroazepino[4,5-b]indole-3(2H)-carboxylate

[1414] Boc₂O (2.7 g, 12 mmol) was added to a solution of(5aS*,10bS*)-10-bromo-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole (2.8 g,12 mmol) in THF (60 mL) followed by 10% aqueous NaOH (15 mL). After 2 h,the reaction was diluted with H₂O and extracted with EtOAc (3×100 mL).The combined organic layers were washed with brine, dried over Na₂SO₄,decanted, and concentrated. The crude orange foam was purified viacolumn chromatography (Biotage, 40M) with heptane/EtOAc (4:1) to give2.6 g (69%) of a white foam: mp 123.5-124.5° C.; ¹H NMR (300 MHz, CDCl₃)δ6.85 (m, 2H), 6.50 (d, J=7.4 Hz, 1H), 4.16 (m, 1H), 3.89 (br s, 1H),3.63 (m, 3H), 3.37 (m, 2H), 2.02 (m, 4H), 1.47 (s, 9H); IR (diffusereflectance) 3335, 2977, 2929, 1672, 1602, 1465, 1421, 1363, 1322, 1274,1246, 1175, 1115, 981, 755 cm⁻¹; MS (CI) m/z 367 (MH⁺), 369, 313, 311,289, 269, 267, 231, 189, 187: Anal. Calcd for C₁₇H₂₃BrN₂O₂: C, 55.59: H,6.31: N, 7.63: found: C, 55.67: H, 6.37: N, 7.57.

[1415] Preparation 132

[1416] Preparation of (5aS*,10bS*)-di(tert-butyl)10-bromo-1,2,4,5,5a,10b-hexahydroazepino[4,5-b]indole-3,6-dicarboxylate

[1417] Boc₂O (4.3 g, 20 mmol) was added to a solution of(5aS*,10bS*)-tert-butyl10-bromo-1,4,5,5a,6,10b-hexahydroazepino[4,5-b]indole-3(2H)-carboxylate(1.5 g, 4.0 mmol) in THF (40 mL) followed by 10% aqueous NaOH (10 mL).After 96 h, the reaction was diluted with H₂O and extracted with EtOAc(3×75 mL). The combined organic layers were washed with brine, driedover Na₂SO₄, decanted, and concentrated. The crude orange foam waspurified via column chromatography (Biotage, 40M) with heptane/EtOAc(95:5) to give 2.6 g (69%) of a white foam: ¹H NMR (300 MHz, CDCl₃)δ7.68 (br s, 1H), 7.06 (m, 2H), 4.56 (m, 1H), 3.75 (m, 1H), 3.46 (m,4H), 2.22 (m, 4H), 1.56 (s, 9H), 1.45 (s, 9H); IR (diffuse reflectance)2975, 1694, 1450, 1423, 1391, 1366, 1346, 1324, 1301, 1275, 1253, 1242,1166, 1148, 775 cm⁻¹; MS (EI) m/z(M⁺), 312, 310, 223, 221, 211, 210,209, 208, 130, 56: Anal. Calcd for C₂₂H₃₁BrN₂O₄: C, 56.53: H, 6.69: N,5.99: found: C, 56.82: H, 6.72: N, 5.91.

Examples 398-451

[1418] The following general procedure for the parallel synthesis of10-aryl substituted azepinoindolines was used to prepare the compoundsof Examples 402-455. The appropriate boronic acid (0.64 mmol) was addedto a 20 mL scintillation vial followed by the addition of a stocksolution of the (5aS*,10bS*)-di(tert-butyl)10-bromo-1,2,4,5,5a,10b-hexahydroazepino[4,5-b]indole-3,6-dicarboxylate(0.10 g, 0.21 mmol) and Pd(Ph₃P)₂Cl₂ (15 mg, 0.021 mmol) in dioxane (1.1mL). Next, 0.5 mL of a stock solution of 2M aqueous Na₂CO₃ was added toeach vial. Nitrogen was blown over the vials for 1 min, then capped,placed in a J-KEM® heater block attached to a Lab-Line® orbit shaker andshaken (300 RPM) at 100° C. overnight. A subset of the reactions wasmonitored by LC/MS. After all the starting acid was consumed in thesereactions, MeOH (5 mL) and Dowex® 50WX2-400 ion-exchange resin (1.25 g)was added to each vial. The reactions were then shaken (300 RPM) at 60°C. until the product was on the resin, based on LC/MS monitoring. Thevials were cooled to rt and transferred with 2×5 mL of CH₂Cl₂/MeOH (3:1)to disposable fritted syringe barrels on a syringe washing station. Theresin was then rinsed with 10 mL of each of the following: MeOH, CH₂Cl₂and MeOH. The syringe barrels were then transferred to a vacuum manifoldand the product was eluted off the resin into 40 mL scintillation vialswith 5×5 mL of MeOH/NH₄OH (3:1). Two different methods were used toisolate the products. Method A consisted of removing the solvent in thevacuum oven overnight at 47° C. Method B involved removing the solventin the vacuum oven overnight at 47° C. followed by purification via prepHPLC. The products were then evaluated by LC/MS.

Example 398

[1419](5aS*,10bS*)-10-(1-Naphthyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1420] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 315.2 (MH⁺).

Example 399

[1421](5aS*,10bS*)-10-(4-Fluorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1422] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 283.2 (MH⁺).

Example 400

[1423](5aS*,10bS*)-10-(4-Methylphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1424] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 279.2 (MH⁺).

Example 401

[1425](5aS*,10bS*)-10-(4-Methoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1426] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 295.2 (MH⁺).

Example 402

[1427](5aS*,10bS*)-10-(3-Methylphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1428] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 279.2 (MH⁺).

Example 403

[1429](5aS*,10bS*)-10-(3-Chloro-4-fluorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1430] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 317.2 (MH⁺).

Example 404

[1431](5aS*,10bS*)-10-[3,5-Bis(trifluoromethyl)phenyl]-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1432] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 401.1 (MH⁺).

Example 405

[1433](5aS*,10bS*)-10-(3,5-Dichlorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1434] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 333.1 (MH⁺).

Example 406

[1435](5aS*,10bS*)-10-(1,1′-Biphenyl-4-yl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1436] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 341.2 (MH⁺).

Example 407

[1437](5aS*,10bS*)-10-(4-Phenoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1438] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 357.2 (MH⁺).

Example 408

[1439](5aS*,10bS*)-10-[3-(Trifluoromethyl)phenyl]-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1440] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 333.2 (MH⁺).

Example 409

[1441](5aS*,10bS*)-10-(3-Methoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1442] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 295.2 (MH⁺).

Example 410

[1443](5aS*,10bS*)-10-(3,5-Dimethylphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1444] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 293.2 (MH⁺).

Example 411

[1445](5aS*,10bS*)-10-(3-Fluorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1446] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 283.2 (MH⁺).

Example 412

[1447](5aS*,10bS*)-10-(2-Naphthyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1448] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 315.2 (MH⁺).

Example 413

[1449](5aS*,10bS*)-10-[2-(Trifluoromethyl)phenyl]-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1450] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method B, thetitle compound was obtained. MS (ESI+) m/z 333.2 (MH⁺).

Example 414

[1451](5aS*,10bS*)-10-(3-Ethoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1452] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 309.2 (MH⁺).

Example 415

[1453](5aS*,10bS*)-10-(4-Ethoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1454] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 309.2 (MH⁺).

Example 416

[1455](5aS*,10bS*)-10-(3,4-Difluorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1456] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 301.2 (MH⁺).

Example 417

[1457](5aS*,10bS*)-10-(4-Ethylphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1458] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 293.2 (MH⁺).

Example 418

[1459](5aS*,10bS*)-10-(2-Phenoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1460] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 357.2 (MH⁺).

Example 419

[1461](5aS*,10bS*)-10-(3,4-Dimethylphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1462] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 293.2 (MH⁺).

Example 420

[1463](5aS*,10bS*)-10-(2,4-Dimethoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1464] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method B, thetitle compound was obtained. MS (ESI+) m/z 325.2 (MH⁺).

Example 421

[1465](5aS*,10bS*)-10-(4-Isopropylphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1466] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 307.3 (MH⁺).

Example 422

[1467](5aS*,10bS*)-4-(1,2,3,4,5,5a,6,10b-Octahydroazepino[4,5-b]indol-10-yl)-N,N-dimethylaniline

[1468] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method B, thetitle compound was obtained. MS (ESI+) m/z 308.2 (MH⁺).

Example 423

[1469](5aS*,10bS*)-10-(3,4-Dichlorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1470] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 333.1 (MH⁺).

Example 424

[1471](5aS*,10bS*)-10-[4-(Trifluoromethoxy)phenyl]-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1472] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 349.2 (MH⁺).

Example 425

[1473](5aS*,10bS*)-1-[4-(1,2,3,4,5,5a,6,10b-Octahydroazepino[4,5-b]indol-10-yl)phenyl]ethanone

[1474] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 307.2 (MH⁺).

Example 426

[1475](5aS*,10bS*)-1-[3-(1,2,3,4,5,5a,6,10b-Octahydroazepino[4,5-b]indol-10-yl)phenyl]ethanone

[1476] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 307.2 (MH⁺).

Example 427

[1477](5aS*,10bS*)-10-(3,4,5-Trimethoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1478] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 355.2 (MH⁺).

Example 428

[1479](5aS*,10bS*)-10-(2,3-Dichlorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1480] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method B, thetitle compound was obtained. MS (ESI+) m/z 333.1 (MH⁺).

Example 429

[1481](5aS*,10bS*)-10-[4-(Benzyloxy)phenyl]-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1482] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 371.2 (MH⁺).

Example 430

[1483](5aS*,10bS*)-10-(2-Fluoro-1,1′-biphenyl-4-yl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1484] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 359.2 (MH⁺).

Example 431

[1485](5aS*,10bs*)-10-(1,1′-Biphenyl-3-yl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1486] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 341.2 (MH⁺).

Example 432

[1487](5aS*,10bS*)-10-(5-Isopropyl-2-methoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1488] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 337.3 (MH⁺).

Example 433

[1489](5aS*,10bS*)-10-[2-(Methylthio)phenyl]-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1490] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 311.2 (MH⁺).

Example 434

[1491](5aS*,10bS*)-10-(2,5-Dimethoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1492] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 325.2 (MH⁺).

Example 435

[1493](5aS*,10bS*)-10-(5-Chloro-2-methoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1494] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 329.2 (MH⁺).

Example 436

[1495](5aS*,10bS*)-3-(1,2,3,4,5,5a,6,10b-Octahydroazepino[4,5-b]indol-10-yl)benzonitrile

[1496] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A; thetitle compound was obtained. MS (ESI+) m/z 290.2 (MH⁺).

Example 437

[1497](5aS*,10bS*)-10-(2,4-Difluorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1498] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method B, thetitle compound was obtained. MS (ESI+) m/z 301.2 (MH⁺).

Example 438

[1499](5aS*,10bS*)-10-[3-(Trifluoromethoxy)phenyl]-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1500] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 349.2 (MH⁺).

Example 439

[1501](5aS*,10bS*)-10-[2-(Benzyloxy)phenyl]-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1502] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 371.2 (MH⁺).

Example 440

[1503](5aS*,10bS*)-10-(2,3-Difluorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1504] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method B, thetitle compound was obtained. MS (ESI+) m/z 301.1 (MH⁺).

Example 441

[1505](5aS*,10bS*)-10-(2,5-Dichlorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1506] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method B, thetitle compound was obtained. MS (ESI+), m/z 333.1 (MH⁺).

Example 442

[1507](5aS*,10bS*)-10-(2,3-Dimethylphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1508] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 293.3 (MH⁺).

Example 443

[1509](5aS*,10bS*)-10-(2,5-Dimethylphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1510] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 293.2 (MH⁺).

Example 444

[1511](5aS*,10bS*)-10-(5-Fluoro-2-methoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1512] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 313.2 (MH⁺).

Example 445

[1513] (5aS*,10bS*)-10-(4-Fluoro-3-methylphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1514] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 297.2 (MH⁺).

Example 446

[1515](5aS*,10bS*)-10-(4-Chloro-2-methylphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1516] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 313.1 (MH⁺).

Example 447

[1517](5aS*,10bS*)-10-(2-Chloro-4-methoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1518] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 329.2 (MH⁺).

Example 448

[1519](5aS*,10bS*)-10-(2-Chloro-4-methylphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1520] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method A, thetitle compound was obtained. MS (ESI+) m/z 313.2 (MH⁺).

Example 449

[1521](5aS*,10bS*)-10-(2-Isopropylphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1522] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method B, thetitle compound was obtained. MS (ESI+) m/z 307.3 (MH⁺).

Example 450

[1523](5aS*,10bS*)-10-(3-tert-Butyl-5-methylphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1524] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method B, thetitle compound was obtained. MS (ESI+) m/z 335.3 (MH⁺).

Example 451

[1525](5aS*,10bS*)-10-(4-Fluoro-2-methylphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1526] Following the general procedure for the parallel synthesis of10-aryl substituted azepinoindolines and using isolation method B, thetitle compound was obtained. MS (ESI+) m/z 297.2 (MH⁺).

Example 452

[1527](5aS*,10bS*)-10-(1-benzofuran-2-yl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1528] A 30-mL shaker vial was charged with di(tert-butyl)10-bromo-1,2,4,5,5a,10b-hexahydroazepino[4,5-b]indole-3,6-dicarboxylate(0.10 g, 0.214 mmol), potassium phosphate (0.068 g, 0.32 mmol),benzo[b]furan-2-boronic acid (0.104 g, 0.642 mmol), and DMF (2 mL). Thevial was purged with N₂, and tetrakis(triphenylphosphine)palladium(0.025 g, 0.02 mmol) was added and the mixture was agitated at 250 RPMwith heating at 80° C. overnight. The mixture was filtered throughCelite, washing with MeOH (3-5 mL), and sulfonic acid resin(DOWEX®50W-X2, washed and dried, 4.8 meq/g dry weight) was added (1 g).The vial was then purged with N₂, capped and agitated at 250 RPM withheating at 65° C. for 36 h. The mixture was filtered through a scinteredfunnel and the resin was washed 1:1 methylene chloride/methanol and thenconsecutively washed with MeOH and THF to ensure that all excess reagentwas removed from the resin (the methanol and THF washes are alternatedto swell and then shrink the resin to help expel reagents from insidethe resin). The resin was then washed with 4M ammonium hydroxide inmethanol (4×2 ml) and THF (2×2 ml) into an accurately weightround-bottomed flask. The filtrate was concentrated to give 0.042 g(65%) of a beige solid, which was dissolved in methylene chloride andcrystallized to give 0.020 g of the title compound as beige solid: MS(EI) m/z 304 (M+), 302, 260, 259, 258, 247, 246, 207, 195, 153; ¹H NMR(CDCl₃) δ7.64 (d, J=7 Hz, 1 H), 7.53 (d, J=8 Hz, 1 H), 7.35-7.22 (m, 3H), 7.15 (t, J=8 Hz, 1 H), 6.63 (d, J=8 Hz, 1 H), 4.38-4.27 (m, 1H),4.16-4.06 (m, 1 H), 3.28-3.22 (m, 1 H), 3.17-3.11 (m, 1 H), 2.95-2.79(m, 2 H), 2.38-2.26 (m, 1 H), 2.10-1.89 (m, 2 H), 1.81-1.72 (m, 1 H)ppm.

Example 453

[1529](5aS*,10bS*)-10-dibenzo[b,d]furan-4-yl-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1530] A 30-mL shaker vial was charged with di(tert-butyl)10-bromo-1,2,4,5,5a,10b-hexahydroazepino[4,5-b]indole-3,6-dicarboxylate(0.10 g, 0.214 mmol), potassium phosphate (0.068 g, 0.32 mmol),4-dibenzofuranboronic acid (0.136 g, 0.642 mmol), and DMF (2 mL). Thevial was purged with N₂, and tetrakis(triphenylphosphine)palladium(0.025 g, 0.02 mmol) was added and the mixture was agitated at 250 RPMwith heating at 80° C. overnight. The mixture was filtered throughCelite, washing with MeOH (3-5 mL), and sulfonic acid resin(DOWEX®50W-X2, washed and dried, 4.8 meq/g dry weight) was added (1 g).The vial was then purged with N₂, capped and agitated at 250 RPM withheating at 65° C. for 72 h. The mixture was filtered through a scinteredfunnel and the resin was washed 1:1 methylene chloride/methanol and thenconsecutively washed with MeOH and THF to ensure that all excess reagentwas removed from the resin (the methanol and THF washes are alternatedto swell and then shrink the resin to help expel reagents from insidethe resin). The resin was then washed with 4M ammonium hydroxide inmethanol (4×2 ml) and THF (2×2 ml) into an accurately weightround-bottomed flask. The filtrate was concentrated to give 0.035 g(47%) of a white solid: MS (EI) m/z 355 (MH+); HPLC rt=3.86 min (95%).

Example 454

[1531](5aS*,10bS*)-10-thien-3-yl-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1532] A 30-mL shaker vial was charged with di(tert-butyl)10-broino-1,2,4,5,5a,10b-hexahydroazepino[4,5-b]indole-3,6-dicarboxylate(0.10 g, 0.214 mmol), potassium phosphate (0.068 g, 0.32 mmol),3-thiopheneboronic acid (0.82 g, 0.642 mmol), and DMF (2 mL). The vialwas purged with N₂, and tetrakis(triphenylphosphine)palladium (0.025 g,0.02 mmol) was added and the mixture was agitated at 250 RPM withheating at 80° C. overnight. The mixture was filtered through Celite,washing with MeOH (3-5 mL), and sulfonic acid resin (DOWEX®50W-X2,washed and dried, 4.8 meq/g dry weight) was added (1 g). The vial wasthen purged with N₂, capped and agitated at 250 RPM with heating at 65°C. for 72 h. The mixture was filtered through a scintered funnel and theresin was washed 1:1 methylene chloride/methanol and then consecutivelywashed with MeOH and THF to ensure that all excess reagent was removedfrom the resin (the methanol and THF washes are alternated to swell andthen shrink the resin to help expel reagents from inside the resin). Theresin was then washed with 4M ammonium hydroxide in methanol (4×2 ml)and THF (2×2 ml) into an accurately weight round-bottomed flask. Thefiltrate was concentrated to give 0.035 g (60%) of a brown oil: MS (EI)m/z 271 (MH+); HPLC rt=2.78 min (100%).

Example 455

[1533](5aS*,10bS*)-10-(1-benzothien-2-yl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1534] A 30-mL shaker vial was charged with di(tert-butyl)10-bromo-1,2,4,5,5a,10b-hexahydroazepino[4,5-b]indole-3,6-dicarboxylate(0.10 g, 0.214 mmol), potassium phosphate (0.068 g, 0.32 mmol),benzothiophene-2-boronic acid (0.114 g, 0.642 mmol), and DMF (2 mL). Thevial was purged with N₂, and tetrakis(triphenylphosphine)palladium(0.025 g, 0.02 mmol) was added and the mixture was agitated at 250 RPMwith heating at 80° C. overnight. The mixture was filtered throughCelite, washing with MeOH (3-5 mL), and sulfonic acid resin(DOWEX®50W-X2, washed and dried, 4.8 meq/g dry weight) was added (1 g).The vial was then purged with N₂, capped and agitated at 250 RPM withheating at 65° C. for 72 h. The mixture was filtered through a sinteredfunnel and the resin was washed 1:1 methylene chloride/methanol and thenconsecutively washed with MeOH and THF to ensure that all excess reagentwas removed from the resin (the methanol and THF washes are alternatedto swell and then shrink the resin to help expel reagents from insidethe resin). The resin was then washed with 4M ammonium hydroxide inmethanol (4×2 ml) and THF (2×2 ml) into an accurately weightround-bottomed flask. The filtrate was concentrated to give 0.040 g(68%) of an amber oil: MS (EI) m/z 321 (MH+); HPLC rt=3.68 min (100%).

Example 456

[1535](5aS*,10bS*)-10-Quinolin-3-yl-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1536] A 30-mL shaker vial was charged with di(tert-butyl)10-bromo-1,2,4,5,5a,10b-hexahydroazepino[4,5-b]indole-3,6-dicarboxylate(0.10 g, 0.214 mmol), potassium phosphate (0.068 g, 0.32 mmol),3-quiniline boronic acid (0.111 g, 0.642 mmol), and DMF (2 mL). The vialwas purged with N₂, and tetrakis(triphenylphosphine)palladium (0.025 g,0.02 mmol) was added and the mixture was agitated at 250 RPM withheating at 80° C. overnight. The mixture was filtered through Celite,washing with MeOH (3-5 mL), and sulfonic acid resin (DOWEX®50W-X2,washed and dried, 4.8 meq/g dry weight) was added (1 g). The vial wasthen purged with N₂, capped and agitated at 250 RPM with heating at 65°C. for 72 h. The mixture was filtered through a scintered funnel and theresin was washed 1:1 methylene chloride/methanol and then consecutivelywashed with MeOH and THF and 2M pyridine/MeOH to ensure that all excessreagent was removed from the resin (the methanol and THF washes arealternated to swell and then shrink the resin to help expel reagentsfrom inside the resin). The resin was then washed with 4M ammoniumhydroxide in methanol (4×2 ml) and THF (2×2 ml) into an accuratelyweight round-bottomed flask. The filtrate was concentrated to give 0.049g (73%) of an amber oil: MS (EI) m/z 316 (MH+); HPLC rt=2.67 min (85%).

Example 457

[1537](5aS*,10bS*)-10-(3-furyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole

[1538] A 30-mL shaker vial was charged with di(tert-butyl)10-bromo-1,2,4,5,5a,10b-hexahydroazepino[4,5-b]indole-3,6-dicarboxylate(0.10 g, 0.214 mmol), potassium phosphate (0.068 g, 0.32 mmol),furan-3-boronic acid (0.072 g, 0.642 mmol), and DMF (2 mL). The vial waspurged with N₂, and tetrakis(triphenylphosphine)-palladium (0.025 g,0.02 mmol) was added and the mixture was agitated at 250 RPM withheating at 80° C. overnight. The mixture was filtered through Celite,washing with MeOH (3-5 mL), and sulfonic acid resin (DOWEX®50W-X2,washed and dried, 4.8 meq/g dry weight) was added (1 g). The vial wasthen purged with N₂, capped and agitated at 250 RPM with heating at 65°C. for 72 h. The mixture was filtered through a scintered funnel and theresin was washed 1:1 methylene chloride/methanol and then consecutivelywashed with MeOH and THF to ensure that all excess reagent was removedfrom the resin (the methanol and THF washes are alternated to swell andthen shrink the resin to help expel reagents from inside the resin). Theresin was then washed with 4M ammonium hydroxide in methanol (4×2 ml)and THF (2×2 ml) into an accurately weight round-bottomed flask. Thefiltrate was concentrated to give 0.038 g (70%) of a pink oil: MS (EI)m/z 255 (MH+); HPLC rt=2.51 min (100%).

Example 458

[1539](5aS*,10bS*)-8,9-Dichloro-6-(2-phenoxyethyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indolehydrochloride

[1540] A solution of8,9-dichloro-6-(2-phenoxyethyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(1.2 g, 3.1 mmol) in TFA (40 mL) was cooled to 0° C. A fresh solution ofNaCNBH₃ (4.9 g, 77 mmol) in MeOH (10 mL) was prepared and added dropwiseat 0° C. After the addition was complete, the reaction was warmed to rtand then heated to 50° C. After 2 h, the reaction was cooled to rt,diluted with water, made basic with 50% aqueous NaOH, and extracted withEtOAc (3×100 mL). The combined organic layers were washed with brine,dried over Na₂SO₄, decanted, and concentrated. The crude material waspurified via column chromatography (Biotage, 40M, SIM) withCH₂Cl₂/MeOH/NH₄OH (976:21:3) to give a crude solid. The hydrochloridesalt was prepared to give 0.17 g (14%) of a tan solid: mp 223.0-223.5°C.; ¹H NMR (DMSO, 300 MHz) δ8.92 (m, 2H), 7.26 (m, 3H), 6.93 (m, 3H),6.75 (s, 1H), 4.09 (m, 3H), 3.65 (m, 2H), 3.46 (m, 2H), 3.08 (m, 3H),2.90 (m, 1H), 2.23 (m 1H), 2.09 (m, 2H); ¹³C NMR (400 MHz, DMSO) δ158.1,151.1, 132.2, 130.0, 129.4, 125.2, 120.6, 117.2, 114.3, 107.0, 65.2,64.7, 44.5, 44.3, 42.3, 42.0, 27.4, 25.6; IR (diffuse reflectance) 2971,2950, 2857, 2840, 2800, 2750, 2718, 2684, 2656, 1595, 1494, 1467, 1245,785, 758 cm⁻¹; HRMS (FAB) calcd for C₂₀H₂₂Cl₂N₂O+H 377.1187, found377.1189; Anal. Calcd for C₂₀H₂₂Cl₂N₂O.HCl: C, 58.06; H, 5.60; N, 6.77;found: C, 57.81; H, 5.65; N, 6.71.

Example 459

[1541](5aS*,10bS*)-9,10-Dichloro-6-(2-phenoxyethyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indolehydrochloride

[1542] A solution of9,10-dichloro-6-(2-phenoxyethyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(0.24 g, 0.64 mmol) in TFA (8 mL) was cooled to 0° C. A fresh solutionof NaCNBH₃ (1.0 g, 16 mmol) in MeOH (2 mL) was prepared and addeddropwise at 0° C. After the addition was complete, the reaction waswarmed to rt and then heated to 50° C. After 2.5 h, the reaction wascooled to rt, diluted with water, made basic with 50% aqueous NaOH, andextracted with EtOAc (3×20 mL). The combined organic layers were washedwith brine, dried over Na₂SO₄, decanted, and concentrated. The crudematerial was purified via column chromatography (Biotage, 40S) withCH₂Cl₂/MeOH/NH₄OH (976:21:3) to give 0.43 g of a crude solid. After thehydrochloride salt was prepared, it was further purified by trituratingwith ether and recrystallization from MeOH/EtOAc to give 0.16 g (59%) ofa white solid: mp 141.6-143.0° C.; ¹H NMR (DMSO, 300 MHz) δ8.79 (br s,2H), 7.28 (m, 3H), 6.93 (m, 3H), 6.63 (d, J=8.5 Hz, 1H), 4.08 (m, 3H),3.65 (m, 2H), 3.12 (m, 2H), 3.00 (m, 1H), 2.36 (m, 1H), 2.17 (m, 1H),2.05 (m, 2H); ¹³C NMR (DMSO) δ158.0, 151.7, 130.3, 129.8, 129.4, 127.0,120.6, 118.1, 114.3, 106.6, 64.9, 64.5, 44.7, 44.7, 43.6, 41.3, 25.3,24.6; IR (diffuse reflectance) 2971, 2950, 2857, 2840, 2800, 2750, 2718,2684, 2656, 1595, 1494, 1467, 1245, 785, 758 cm⁻¹; HRMS (FAB) calcd forC₂₀H₂₂Cl₂N₂O+H 377.1187, found 377.1189; Anal. Calcd forC₂₀H₂₂Cl₂N₂O.HCl: C, 58.06; H, 5.60; N, 6.77; found: C, 57.81; H, 5.65;N, 6.71.

[1543] Preparation 133

[1544] Preparation of tert-butyl(5aS*,10bS*)-9,10-dichloro-6-(2-phenoxyethyl)-1,4,5,5a,6,10b-hexahydroazepino[4,5-b]indole-3(2H)-carboxylate

[1545] Boc₂O (0.59 g, 2.7 mmol) was added to a solution of9,10-dichloro-6-(2-phenoxyethyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole(0.85 g, 2.3 mmol) in THF (32 mL) followed by 10% aqueous NaOH (8 mL).After 2 h, the reaction was diluted with H₂O (35 mL) and extracted withEtOAc (3×40 mL). The combined organic layers were washed with brine,dried over Na₂SO₄, decanted, and concentrated. The crude product waspurified via column chromatography (Biotage, 40M) with heptane/EtOAc(4:1) to give 0.60 g of the racemic product that was submitted forseparation of the two enantiomers.

[1546] Preparation 134

[1547] Preparation of tert-butyl(5aS*,10bS*)-9,10-dichloro-6-(2-phenoxyethyl)-1,4,5,5a,6,10b-hexahydroazepino[4,5-b]indole-3(2H)-carboxylateand tert-butyl(5aR,10bR)-9,10-dichloro-6-(2-phenoxyethyl)-1,4,5,Sa,6,10b-hexahydroazepino[4,5-b]indole-3(2H)-carboxylate

[1548] The racemic tert-butyl(5aS*,10bS*)-9,10-dichloro-6-(2-phenoxyethyl)-1,4,5,5a,6,10b-hexahydroazepino[4,5-b]indole-3(2H)-carboxylatewas separated on a Chiralpak AD column (0.46×25 cm; 0.5 mL/min; 5%isopropanol/heptane; 270 nm) to give the faster eluting enantiomer at17.99 min with 99% ee and the slower eluting at 25.16 min with 97% ee.

Example 460

[1549](−)-9,10-Dichloro-6-(2-phenoxyethyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indolehydrochloride (cis ring fusion)

[1550] TFA (1.01 ml, 13 mmol) was added to a solution of the fastereluting resolved tert-butyl9,10-dichloro-6-(2-phenoxyethyl)-1,4,5,5a,6,10b-hexahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.31 g, 0.66 mmol) in CH₂Cl₂ (7 mL). After 4 h, the reaction was madebasic with 10% aqueous NaOH, and extracted with CH₂Cl₂ (3×25 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄,decanted, and concentrated. The hydrochloride salt was prepared viacrystallization from EtOAc/heptane of the crude material and then wasfurther purified by recrystallization from MeOHF/EtOAc to give 18 mg(7%, 100% ee) of a white solid: mp 100.5-104.0° C.; ¹H NMR (DMSO, 300MHz) δ8.92 (br s, 2H), 7.26 (m, 3H), 6.92 (m, 3H), 6.62 (d, J=8.5 Hz,1H), 4.08 (m, 3H), 3.67 (m, 2H), 3.07 (m, 3H), 2.38 (m, 1H) 2.20 (m,1H), 2.06 (m, 2H); IR (diffuse reflectance) 2954, 2846, 2778, 2752,1594, 1497, 1460, 1291, 1273, 1244, 1226, 811, 803, 752, 695 cm⁻¹; MS(EI) m/z 376 (M⁺), 321, 320, 319, 242, 240, 228, 226, 77, 56; HRMS (FAB)calcd for C₂₀H₂₂Cl₂N₂O+H 377.1187, found 377.1179.

Example 461

[1551](+)-9,10-Dichloro-6-(2-phenoxyethyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indolehydrochloride (cis ring fusion)

[1552] TFA (0.85 ml, 11 mmol) was added to a solution of the slowereluting resolved tert-butyl9,10-dichloro-6-(2-phenoxyethyl)-1,4,5,5a,6,10b-hexahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.26 g, 0.55 mmol) in CH₂Cl₂ (7 mL). After 5 h, the reaction was madebasic with 10% aqueous NaOH, and extracted with CH₂Cl₂ (3×25 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄,decanted, and concentrated. The hydrochloride salt was prepared viacrystallization from EtOAc/heptane of the crude material and then wasfurther purified by recrystallization from MeOH/EtOAc to give 44 mg(19%, 96% ee) of a white solid: mp 110.5-117.0° C.; ¹H NMR (DMSO, 300MHz) δ9.10 (br s, 2H), 7.27 (m, 3H), 6.92 (m, 3H), 6.62 (d, J=8.5 Hz,1H), 4.08 (m, 3H), 3.63 (m, 2H), 3.41 (m, 1H), 3.27 (m, 3.10 (m, 2H),3.00 (m, 1H), 2.37 (m, 1H), 2.22 (m, 1H), 2.08 (m, 2H); IR (diffusereflectance) 2955, 2881, 2850, 2778, 2745, 1595, 1497, 1459, 1291, 1273,1244, 1226, 811, 752, 695 cm⁻¹; MS (EI) m/z 376 (M⁺), 378, 321, 320,319, 318, 242, 240, 228, 226; HRMS (FAB) calcd for C₂₀H₂₂Cl₂N₂O+H377.1187, found 377.1195.

Example 462

[1553](SaS*,10bS*)-7,10-Dichloro-6-(2-phenoxyethyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indolehydrochloride

[1554] A solution of7,10-dichloro-6-(2-phenoxyethyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(0.36 g, 0.96 mmol) in TFA (12 mL) was cooled to 0° C. A fresh solutionof NaCNBH₃ (1.5 g, 24 mmol) in MeOH (3 mL) was prepared and addeddropwise at 0° C. After the addition was complete, the reaction waswarmed to rt and then heated to 50° C. After 3 h, the reaction wascooled to rt, diluted with water, made basic with 50% aqueous NaOH, andextracted with CHCl₃ (3×30 mL). The combined organic layers were washedwith brine, dried over Na₂SO₄, decanted, and concentrated. Thehydrochloride salt was prepared from the crude solid to give 98 mg (27%)of a white solid: mp 248.5-251.5° C.; ¹H NMR (DMSO, 300 MHz) δ8.91 (brs, 2H), 7.27 (m, 2H), 7.12 (d, J=8.7 Hz, 1H), 6.91 (m, 3H), 6.72 (d,J=8.7 Hz, 1H), 4.14 (m, 4H), 3.76 (m, 1H), 3.62 (m, 1H), 3.10 (m, 2H),2.96 (m, 1H), 2.36 (m, 1H), 2.08 (m, 3H); ¹³C NMR (400 MHz, DMSO)δ158.0, 147.8, 131.8, 131.5, 129.4, 128.0, 120.7, 119.7, 114.2, 112.0,65.7, 65.4, 45.7, 44.7, 42.9, 41.7, 25.7, 25.0; IR (diffuse reflectance)2960, 2800, 2779, 2741, 2716, 2694, 2687, 2660, 1590, 1465, 1427, 1246,1234, 798, 757 cm⁻¹; MS (CI) m/z 377 (MH⁺), 380, 379, 378, 377, 343,223, 121, 96, 61, 52; % Water (KF): 0.11; Anal. Calcd forC₂₀H₂₂Cl₂N₂O.HCl: C, 58.06; H, 5.60; N, 6.77; Cl, 25.70; Found: C,57.84; H, 5.64; N, 6.73; Found; Cl, 25.07.

Example 463

[1555](5aS*,10bS*)-7,8-Dichloro-6-(2-phenoxyethyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indolehydrochloride

[1556] A solution of7,8-dichloro-6-(2-phenoxyethyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(0.25 g, 0.67 mmol) in TFA (7.5 mL) was cooled to 0° C. A fresh solutionof NaCNBH₃ (0.21 g, 3.3 mmol) in MeOH (2.5 mL) was prepared and addeddropwise at 0° C. After 2.5 h, the reaction was made basic with 25%aqueous NaOH, and extracted with CHCl₃ (3×25 mL). The combined organiclayers were washed with brine, dried over Na₂SO₄, decanted, andconcentrated. The crude material was purified via column chromatography(Biotage, 40S) with CH₂Cl₂/MeOH/NH₄OH (976:21:3) followed by thepreparation of the hydrochloride salt to give 0.19 mg (67%) of a whitesolid: mp 160.5-162.5° C.; ¹H NMR (DMSO, 300 MHz) δ8.86 (bs, 1H), 8.74(bs, 1H), 7.26 (m, 2H), 7.01-6.86 (m, 5H), 4.27-4.04 (m, 4H), 3.84 (td,J=10, 4.3 Hz, 1H), 3.66 (m, 1H), 3.23-2.90 (m, 4H), 2.25-1.91 (m, 4H);IR (diffuse reflectance) 2926, 2908, 2852, 1602, 1574, 1451, 1370, 1291,1282, 1260, 1139, 906, 832, 772, 718 cm⁻¹; MS (EI) m/z 376 (M+), 269,240, 228, 226, 214, 135, 91, 77, 56, 51; Anal. Calcd forC₂₀H₂₂Cl₂N₂O.HCl: C, 58.06; H, 5.60; N, 6.77; Cl, 25.70; found: C,57.76; H, 5.96; N, 6.59.

Example 464

[1557](5aS*,10bS*)-8,10-Dichloro-6-(2-phenoxyethyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indolehydrochloride

[1558] A solution of8,10-dichloro-6-(2-phenoxyethyl)-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole(0.20 g, 0.53 mmol) in TFA (8 mL) was cooled to 0° C. A fresh solutionof NaCNBH₃ (0.84 g, 13 mmol) in MeOH (2 mL) was prepared and addeddropwise at 0° C. After the addition was complete, the reaction waswarmed to rt and then heated to 50° C. After 2.5 h, the reaction wascooled to rt, made basic with 50% aqueous NaOH, and extracted with CHCl₃(3×20 mL). The combined organic layers were washed with brine, driedover Na₂SO₄, decanted, and concentrated. The crude material was purifiedvia column chromatography (Biotage, 40S) with CH₂Cl₂/MeOH/NH₄OH(976:21:3) followed by the preparation of the hydrochloride salt to give0.14 mg (64%) of a beige solid: mp 133.5-135° C.; ¹H NMR (DMSO, 300 MHz)6 8.89 (bs, 2H), 7.29 (dd, J=8.6, 7.4 Hz, 2H), 6.91 (m, 3H), 6.68 (d,J=1.7 Hz, 1H), 6.65 (d, J=1.7 Hz, 1H); 4.18 (m, 1H), 4.09 (m, 2H), 3.67(m, 2H), 3.41 (m, 1H), 3.23 (m, 1H), 3.11 (m, 1H), 2.98 (m, 1H), 2.36(m, 1H), 2.17 (m, 1H), 2.06 (m, 2H); IR (diffuse reflectance) 2926,2908, 2852, 1602, 1574, 1451, 1370, 1291, 1282, 1260, 1139, 906, 832,772, 718 cm ⁻¹; MS (EI) m/z 390 (M+), 321, 319, 283, 242, 240, 228, 226,77, 65, 56; HRMS (FAB) calcd for C₂₀H₂₂Cl₂N₂O+H 377.1187, found377.1188.

[1559] Preparation 135

[1560] Preparation of ethyl(9,10-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1 H)-yl)acetate

[1561] TFA (10.5 mL, 136 mmol) was added to a solution of tert-butyl9,10-dichloro-6-(2-ethoxy-2-oxoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate(3.0 g, 6.8 mmol) in CH₂Cl₂ (70 mL). After 5 h, the reaction was madebasic with 10% aqueous NaOH and extracted with CH₂Cl₂ (3×50 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄,decanted, and concentrated to give 2.4 g of the crude yellow oil: 1H NMR(300 MHz, CDCl₃) δ7.16 (d, J=8.7 Hz, 1H), 6.97 (d, J=8.7 Hz, 1H), 4.75(s, 2H), 4.19 (q, J=7.1 Hz, 2H), 3.45 (m, 2H), 3.10 (t, J=5.1 Hz, 4H),2.87 (m, 2H 2.28 (br s, 1H) 1.25 (m, 3H); IR (diffuse reflectance) 2979,2958, 2939, 2904, 2837, 2816, 2797, 2766, 2644, 1744, 1449, 1372, 1279,1204, 1160 cm⁻¹;MS (EI) m/z 340 (M⁺), 305, 300, 298, 270, 226, 224, 154,149, 127; HRMS (FAB) calcd for C₁₆H₁₈CL₂N₂O₂+H 341.0823, found 341.0818.

[1562] Preparation 136

[1563] Preparation of (5aS*,10bS*)-ethyl(9,10-dichloro-2,3,4,5,5a,10b-hexahydroazepino[4,5-b]indol-6(1H)-yl)acetate

[1564] A solution of (5aS*, 10bS*)-ethyl(9,10-dichloro-2,3,4,5-tetrahydroazepino[4,5-b]indol-6(1H)-yl)acetate(2.2 g, 6.4 mmol) in TFA (40 mL) was cooled to 0° C. A fresh solution ofNaCNBH₃ (5.0 g, 80 mmol) in MeOH (10 mL) was prepared and added dropwiseat 0° C. After the addition was complete, the reaction was warmed to rtand then heated to 50° C. After 1.5 h, the reaction was cooled to rt,diluted with water, made basic with 50% aqueous NaOH, and extracted withCHCl₃. The combined organic layers were washed with brine, dried overNa₂SO₄, decanted, and concentrated to a crude yellow foam: ¹H NMR (300MHz, CDCl₃) δ8.90 (br s, 1H), 7.18 (m, 1H), 6.23 (m, 1H), 4.20 (m, 3H),3.91 (m, 1H), 3.67 (m, 2H), 3.45 (m, 1H), 3.25 (m, 1H), 2.86 (m, 1H),2.30 (m, 5H), 1.25 (t, J=7.1 Hz, 3H); IR (diffuse reflectance)2983,2959,2866,1739, 1676,1595,1466, 1429,1393,1373,1305, 1277,1201,1140, 799 cm⁻¹; MS (EI) m/z 342 (M⁺), 287, 286, 285, 284, 228, 226, 214,212, 56; HRMS (FAB) calcd for C₁₆H₂₀CL₂N₂O₂+H 343.0980, found 343.0970.

[1565] Preparation 137

[1566] Preparation of tert-butyl(5aS*,10bS*)-9,10-dichloro-6-(2-ethoxy-2-oxoethyl)-1,4,5,5a,6,10b-hexahydroazepino[4,5-b]indole-3(2H)-carboxylate

[1567] Boc₂O (1.8 g, 8.4 mmol) was added to a solution of ethyl(5aS*,10bS*)-(9,10-dichloro-2,3,4,5,5a,10b-hexahydroazepino[4,5-b]indol-6(1H)-yl)acetate (2.4 g, 7.0 mmol) in THF (40 mL) followed by 10% aqueousNaOH (10 mL). After 2 h, the reaction was diluted with H₂O (50 mL) andextracted with EtOAc (3×100 mL). The combined organic layers were washedwith brine, dried over Na₂SO₄, decanted, and concentrated. The crudeproduct was purified via column chromatography (Biotage, 40M) withheptane/EtOAc (4:1) to give 1.2 g of a white foam: ¹H NMR (300 MHz,CDCl₃) δ7.13 (d, J=8.4 Hz, 1H), 6.19 (d, J=8.4 Hz, 1H), 4.15 (q, J=7.1Hz, 3H), 3.93 (d, J=17.9 Hz, 1H), 3.71 (d, J=17.9 Hz, 1H), 3.47 (m, 5H),2.14 (m, 1H), 1.99 (m, 3H), 1.46 (s, 9H), 1.24 (t, J=7.1 Hz, 3H); IR(diffuse reflectance) 1687, 1505, 1468, 1414, 1366, 1296, 1268, 1248,1218, 1169, 1114, 1105, 865, 827, 746 cm⁻¹; MS (ESP) m/z 493 (MH⁺), 516,515, 366, 364, 265, 253, 138, 94, 91, 85; Anal. Calcd forC₂₅H₂₇Cl₂FN₂O₃: C, 60.86; H, 5.51; N, 5.68; found: C, 60.91; H, 5.61; N,5.64.

[1568] Preparation 138

[1569] Preparation of [3-(tert-butoxycarbonyl)(5aS*,10bS*)-9,10-dichloro-2,3,4,5,5a,10b-hexahydroazepino[4,5-b]indol-6(1H)-yl]acetic acid

[1570] A solution of KOH (0.16 g, 2.8 mmol) in H₂O (10 mL) was added toa solution of tert-butyl(5aS*,10bS*)-9,10-dichloro-6-(2-ethoxy-2-oxoethyl)-1,4,5,5a,6,10b-hexahydroazepino[4,5-b]indole-3(2H)-carboxylate(0.96 g, 2.17 mmol) in THF (15 mL). The mixture was heated at 60° C. for2 h. The reaction was then cooled to rt, acidified with 10% aqueous HCl,and extracted with EtOAc (3×30 mL). The combined organic extracts werewashed with brine, dried over Na₂SO₄, decanted, and concentrated to givecrude white foam (0.90 g): ¹H NMR (300 MHz, CDCl₃) δ7.14 (d, J=8.3 Hz,1H), 6.21 (d, J=8.4 Hz, 1H), 4.08 (m, 1H), 3.93 (d, J=18.3 Hz, 1H), 3.76(d, J=18.3 Hz, 1H), 3.47 (m, 5H), 2.04 (m, 4H), 1.44 (s, 9H); HRMS (FAB)calcd for Cl₉H₂₄CL₂N₂O₄+H 415.1191, found 415.1198.

[1571] Preparation 139

[1572] Preparation of tert-butyl (5aS*,10bS*)-9,10-dichloro-6-{2-[(2,3-dimethylphenyl)amino]-2-oxoethyl}-1,4,5,5a,6,10b-hexahydroazepino[4,5-b]indole-3(2H)-carboxylate

[1573] EEDQ (0.57 g, 2.3 mmol) and 2,3-dimethylaniline (0.28 g, 2.3mmol) were added to a solution of [3-(tert-butoxycarbonyl)(5aS*,10bS*)-9,10-dichloro-2,3,4,5,5a,10b-hexahydroazepino[4,5-b]indol-6(1H)-yl]acetic acid (0.80 g, 1.9 mmol)in THF (20 mL). The reaction was heated to 50° C., cooled to rt after 6h, and concentrated. The crude product was purified via columnchromatography (Biotage, 40M) with CH₂Cl₂/MeOH (99:1) followed bycrystallization from EtOAc/heptane to give a white solid: mp145.5-146.0° C.; ¹H NMR (CDCl₃, 300 MHz) δ8.49 (br s, 1H), 7.31 (m, 1H),7.21 (d, J=8.3 Hz, 1H), 7.13 (m, 1H), 7.00 (d, J=7.5 Hz, 1H), 6.37 (d,J=8.4 Hz, 1H), 3.89 (m, 2H), 3.78 (m, 2H), 3.66 (m, 1H), 3.58 (m, 1H),3.33 (m, 2H), 2.34 (m, 1H), 2.27(s, 3H), 2.17 (m, 1H), 2.02 (s, 3H),1.90 (m, 2H), 1.45 (s, 9H); IR (diffuse reflectance) 1692, 1661, 1596,1517, 1499, 1465, 1428, 1365, 1329, 1265, 1252, 1241, 1177, 1142, 795 cm⁻¹; MS (EI) m/z 517 (M⁺), 519, 315, 313, 269, 228, 226, 57, 56, 55;Anal. Calcd for C₂₇H₃₃Cl₂N₃O₃: C, 62.55; H, 6.41; N, 8.10; found: C,62.53; H, 6.43; N, 8.08.

Example 465

[1574](5aS*,10bS*)-2-(9,10-dichloro-2,3,4,5,5a,10b-hexahydroazepino[4,5-b]indol-6(1H)-yl)-N-(2,3-dimethylphenyl)acetamide hydrochloride

[1575] TFA (0.60 mL, 7.7 mmol) was added to a solution of tert-butyl(5aS*,10bS*)-9,10-dichloro-6-{2-[(2,3-dimethylphenyl)amino]-2-oxoethyl}-1,4,5,5a,6,10b-hexahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.20g, 0.39 mmol) in CH₂CI₂ (7 mL). The reaction was quenched with 10%aqueous NaOH (5 mL) after 2.5 h and extracted with CH₂Cl₂ (3×25 mL). Thecombined organic layers were washed with brine, dried over Na₂SO₄,decanted, and concentrated. The crude yellow foam (0.15 g) was purifiedvia column chromatography (Biotage, 40S) with CH₂Cl₂/MeOH/NH₄OH(976:21:3) followed by the preparation of the hydrochloride salt to give67 mg (38%) of an off white solid: mp 238.5-241.0° C.; ¹H NMR (DMSO, 300MHz) δ9.60 (s, 1H), 8.92 (br s, 2H), 7.30 (d, J=8.4 Hz, 1H), 7.13 (m,1H), 7.03 (m, 2H), 6.54 (d, J=8.7 Hz, 1H), 4.24 (m, 1H), 4.16 (d, J=17.1Hz, 1H), 3.87 (d, J=17.1 Hz, 1H), 3.71 (m, 1H), 3.35 (m, 2H 3.08 (m,3H), 2.34 (m, 1H), 2.24 (m, 3H), 2.12 (m, 5H); IR (diffuse reflectance)2969, 2955, 2938, 2823, 2796, 2772, 2755, 2727, 1676, 1527, 1464, 1285,1274, 806, 787 cm⁻¹; MS (EI) m/z 417 (M⁺), 419, 226, 120, 106, 105, 9,77, 76, 56; HRMS (FAB) calcd for C₂₂H₂₅CL₂N₃O+H 418.1453, found418.1439.

[1576] Efficacy Data

[1577] The ability of a compound of the invention to act as a 5-HTreceptor agonist or antagonist can also be determined using in vitro andin vivo assays that are known in the art. The invention providescompounds of formula (I) that act as either agonists or as antagonistsof one or more 5-HT receptor subtypes. The compounds of the inventionare 5-HT ligands, which typically displace >50% of a radiolabeled testligand from one or more 5-HT receptor subtype at a concentration of 1μM. The procedures used for testing such displacement are well known andwould be readily available to one skilled in the art. For example, seeL. W. Fitzgerald et al., Mol. Pharmacol, 2000, 57, 1, 75-81; and D. B.Wainscott, et al., J. Pharmacol Exp Ther, 1996, 276, 2, 720-727.

[1578] All cited publications, patents, and patent documents areincorporated by reference herein, as though individually incorporated byreference. The invention has been described with reference to variousspecific and preferred embodiments and techniques. However, it should beunderstood that many variations and modifications;may be made whileremaining within the spirit and scope of the invention.

What is claimed is:
 1. A compound of Formula (I):

wherein: R¹ is selected from the group consisting of hydrogen,C₁₋₈alkyl, and C₁₋₈hydrocarbylene Ar; each R², independently, isselected from the group consisting of C₁₋₈alkyl, and OH; R³ is hydrogen,C₁₋₈alkyl, Ar, Het, R⁷C(═O)—, R⁷OC(═O)—, R⁵R⁶NC(═O)—, R⁷C(═S)—,R⁷SC(═O)—, R⁵R⁶NC(═S)—, R⁷SO₂—, R⁵R⁶NSO₂—, R⁷S(═O)—, R⁵R⁶NS(═O)—,R^(c)C₁₋₈hydrocarbylene—, or R^(c)C₁₋₈hydrocarbyleneC(═O)—; each R⁴,independently, is selected from the group consisting of Ar, C₁₋₈alkyl,ArO—, C₁₋₈alkoxy, Het, halo, OH, CN, NO₂, CF₃, CF₃O, NR^(a)R^(b),N═CR^(a)R^(b), R⁷S, C₁₋₈hydrocarbyleneAr, and C₁₋₈hydrocarbyleneOR^(a);each R⁵ and R⁶ is independently hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl,C₂₋₈alkynyl, haloC₁₋₈alkyl, C₃₋₈cycloalkenyl, Ar, or—C₁₋₈hydrocarbyleneAr; or R⁵ and R⁶ together with the nitrogen to whichthey are attached form a pyrrolidino, piperidino, morpholino, orthiomorpholino ring; each R⁷ is independently hydrogen, C₁₋₈alkyl,C₂₋₈alkenyl, C₂₋₈alkynyl, haloC₁₋₈alkyl, C₃₋₈cycloalkenyl, Ar, or—C₁₋₈hydrocarbyleneAr; R^(a) and R^(b), independently, are selected fromthe group consisting of hydrogen, C₁₋₈alkyl, Ar, C₁₋₃hydrocarbyleneAr,SO₂Ar, SO₂C₁₋₄alkyl, (C₃₋₈cycloalkyl)C₁₋₈alkyl, and Het; R^(c) is Ar,Het, R⁷CO₂—, R⁷C(═O)—, R⁷OC(═O)—, R⁷O—, R⁷C₁₋₈alkyleneO—, R⁷S—,R⁷C(═S)—, R⁷S(═O)—, R⁷S(═O)₂—, R⁷SC(═O)—, R⁷C(═O)N(R⁷)—, R⁷C(═S)N(R⁷)—,R⁵R⁶N—, R⁵R⁶NC(═O)—, R⁵R⁶NC(═S)—, R⁵R⁶NS(═O)—, R^(5R) ⁶NSO₂—,R⁷S(═O)N(R⁷)—, R⁷SO₂N(R⁷)—, or R⁷N(R⁷)C(═O) N(R⁷)—; each Ar isindependently aryl or heteroaryl; p is 0, 1, 2, 3, or 4; and q is 0, 1,2, 3, 4, 5, 6, 7, 8, 9, or 10; wherein any Ar of R¹, R³-R⁷, R^(a), R^(b)and R^(c) is optionally substituted with one or more (e.g. 1, 2, 3, 4,or 5) substituents independently selected from halo, CN, NO₂, OR^(e),methylenedioxy, ethylenedioxy, CF₃, OCF₃, SR^(e), SO₂R^(e), NR^(f)R^(g),CONR^(f)R^(g), COR^(e), R^(e), and C₁₋₈hydrocarbyleneR^(d); each R^(d)is independently hydroxy, C₁₋₈alkoxy, cyano, SR^(h), or C(═O)R^(h); eachR^(e) is independently selected from the group consisting of hydrogen,C₁₋₈alkyl, Ar, C₁₋₃hydrocarbyleneAr, SO₂Ar, SO₂C₁₋₄alkyl,(C₃₋₈cycloalkyl)C₁₋₈alkyl, and Het; wherein any Ar of R^(e) isoptionally substituted with one or more (e.g. 1, 2, 3, 4, or 5)substituents independently selected from halo, CN, NO₂, OR^(d),methylenedioxy, ethylenedioxy, CF₃, OCF₃, SR^(f), SO₂R^(f), NR^(f)R^(g),CONR^(f)R^(g), COR^(f), R^(f), and C₁₋₈hydrocarbyleneR^(d); each R^(f)and R^(g), is independently selected from the group consisting ofhydrogen, C₁₋₈alkyl, Ar, C₁₋₃hydrocarbyleneAr, SO₂Ar, SO₂C₁₋₄alkyl,(C₃₋₈cycloalkyl)C₁₋₈alkyl, and Het; and each R^(h) is independentlyhydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, haloC₁₋₈alkyl,C₃₋₈cycloalkenyl, phenyl, or —C₁₋₈hydrocarbylene(phenyl); or apharmaceutically acceptable salt thereof; provided that when (a) R¹ ismethyl; and (b) R³ is hydrogen or —(CH₂)₃NR⁵R⁶, wherein R⁵ and R⁶, areeach methyl; then p and q are not each
 0. 2. The compound of claim 1wherein R¹ is hydrogen.
 3. The compound of claim 1 wherein q is 2, 3, or4.
 4. The compound of claim 1 wherein q is
 1. 5. The compound of claim 1wherein q is
 0. 6. The compound of claim 1 wherein R³ is hydrogen,C₁₋₈alkyl, R⁵R⁶NC(═O)CH₂—, R⁷SC₁₋₈alkylene, or aryloxy(CH₂)₂—.
 7. Thecompound of claim 1, wherein R³ is hydrogen.
 8. The compound of claim 1wherein R³ is C₁₋₈alkyl, R⁵R⁶NC(═O)CH₂— or aryloxy(CH₂)₂—.
 9. Thecompound of claim 1 wherein R³ is: 2-(3-methoxyphenoxy)ethyl,2-(3-nitrophenoxy)ethyl, 2-(3-isopropylphenoxy)ethyl,2-(4-pyridyloxy)ethyl, 3-phenoxypropyl, 3-(3-chlorophenoxy)propyl,3-(4-fluorophenoxy)propyl, 2-phenoxyethyl,N-(2,3-dimethylphenyl)amino-carbonylmethyl,N-(3-methylphenyl)aminocarbonylmethyl,N-(2-fluoro-4-methylphenyl)aminocarbonylmethyl,N-mesitylaminocarbonylmethyl, N-(4-methoxyphenyl)aminocarbonylmethyl,N-(phenyl)aminocarbonylmethyl, N-(4-fluorophenyl)aminocarbonylmethyl,N-(3-nitrophenyl)aminocarbonylmethyl,N-(3-methoxyphenyl)aminocarbonylmethyl,N-(4-cyanophenyl)aminocarbonylmethyl,N-(3,5-dimethoxyphenyl)aminocarbonylmethyl,N-(2,4-dimethoxyphenyl)aminocarbonylmethyl,N-(3-chloro-4-fluorophenyl)aminocarbonylmethyl, 2-anilinoethyl,1H-benzimidazol-2-ylmethyl, isobutoxycarbonylmethyl, carboxymethyl,N,N-dimethylaminocarbonylmethyl, aminocarbonylmethyl,2-(phenylsulfinyl)ethyl, 2-(phenylsulfonyl)ethyl, 2-hydroxyethyl,2-(4-chlorophenoxy)ethyl, 2-(4-fluorophenoxy)ethyl, 2-(phenylthio)ethyl,2-aminoethyl, 2-(anilinocarbonylamino)-ethyl, 2-(benzoylamino)ethyl,2-(phenylsulfonylamino)ethyl, N-(4-methoxyphenyl)aminocarbonylethyl,N-phenylaminocarbonylmethyl, N-(2-pyridyl)aminocarbonylmethyl,N-(4-methoxyphenyl)aminocarbonylmethyl,N-(2,3-dimethylphenyl)aminocarbonylmethyl,N-(5,6,7,8-tetrahydro-1-naphthalenyl)aminocarbonylmethyl,3-ethylanilinocarbonylmethyl, 3-isopropylanilinocarbonylmethyl,N-(3-tert-butylphenyl)aminocarbonylmethyl, N-(1,3-benzothiazol-2-yl)aminocarbonylmethyl, N-(4-methyl-1,3-thiazol-2-yl)aminocarbonylmethyl,N-(5-methyl-1,3-thiazol-2-yl)aminocarbonylmethyl,N-(4-tert-butyl-1,3-thiazol-2-yl)aminocarbonylmethyl,N-(4-phenyl-1,3-thiazol-2-yl)aminocarbonylmethyl, 3-phenylpropyl,2-phenoxyethyl, 2-(4-chlorophenoxy)ethyl, 2-(4-fluorophenoxy)ethyl,2-(5,7-dibromo-8-quinolinyloxy)ethyl, 2-(8-quinolinyloxy)ethyl,2-(5-isoquinolinyloxy)ethyl, 2-(5-quinolinyloxy)ethyl,2-(5,6,7,8-tetrahydro-1-naphthalenyloxy)ethyl,2-(1,3-benzodioxol-5-yloxy)ethyl, 2-(1H-indol-4-yloxy)ethyl,2-(5,6,7,8-tetrahydro-2-naphthalenyloxy)ethyl, 2-(7-quinolinyloxy)ethyl,2-[(5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-1-yl)oxy]ethyl,N-(3-chloro-2-methylphenyl)aminocarbonylmethyl,N-[2-methyl-3-(trifluoromethyl)phenyl]aminocarbonylmethyl,N-(5,6,7,8-tetrahydronaphthalen-1-yl)aminocarbonylmethyl,N-(4-methyl-1,3-thiazol-2-yl)aminocarbonylmethyl,N-(1,3-dihydro-2-benzofuran-4-yl)aminocarbonylmethyl,N-(4-methoxyphenyl)aminocarbonylmethyl,N-(3-pyridyl)aminocarbonylmethyl,N-(4-methyl-1,3-thiazol-2-yl)amninocarbonylmethyl, or2-(5,6,7,8-tetrahydronaphthalen-1-yloxy)ethyl.
 10. The compound of claim1 wherein p is 1, 2, or
 3. 11. The compound of claim 1 wherein p is 0.12. The compound of claim 1 wherein R⁴ is phenyl, optionally substitutedat the 2-position of the phenyl.
 13. The compound of claim 1 wherein R⁴is 2-ethoxyphenyl, or 2-chliorophenyl.
 14. The compound of claim 1wherein R⁴ is aryl, substituted at the 10-position of formula (I). 15.The compound of claim 1 wherein R⁴ is: 5-pyrimidinyl,3,4-dimethoxyphenyl, 3,5-difluorophenyl, 4-n-butyloxyphenyl,4-trifluoromethoxyphenyl, 3,4-dichlorophenyl, 2-naphthyl, 4-pyridinyl,bromo, benzhydrilideneamino, amino, N-(phenylsulfonyl)amino, phenoxy,3-(phenoxy)propyl, 3-(2-naphthyloxy)propyl, 3-(1-naphthyloxy)propyl,3-([1,1′-biphenyl]-4-yloxy)propyl, 3-(3-methoxyphonoxy)propyl,3-(4-methoxyphenoxy)propyl, 3-(4-chlorophenoxy)propyl,3-(3-chlorophenoxy)propyl, 3-(2-chlorophenoxy)propyl,3-(2,4-dichlorophenoxy)propyl, 3-(2,5-dichlorophenoxy)propyl,3-(4-fluorophenoxy)propyl, 3-(4-methylphenoxy)propyl,3-(4-cyanophenoxy)propyl, 3-(pyridin-2-yloxy)propyl,3-(2-bromophenoxy)propyl, 3-(2-iodophenoxy)propyl,3-(2-ethylphenoxy)propyl, 3-(2-isopropylphenoxy)propyl,3-(2-cyanophenoxy)propyl, 3-(pyridin-3yloxy)propyl,3-(3-fluorophenoxy)propyl, 3-(3-bromophenoxy)propyl,3-(3-iodophenoxy)propyl, 3-(3-isopropylphenoxy)propyl,3-[3-(trifluoromethyl)phenoxy]propyl,3-[3-(trifluoromethoxy)phenoxy]propyl, 3-(3-ethylphenoxy)propyl,3-(3-tert-butylphenoxy)propyl, 3-(pyridin-4yloxy)propyl,3-(4-methoxyphenoxy)propyl, 3-[4-(benzyloxy)phenoxy]propyl,3-(4-bromophenoxy)propyl, 3-(4-iodophenoxy)propyl,3-(4-ethylphenoxy)propyl, 3-(4-tert-butylphenoxy)propyl,3-[4′-(bromo[1,1′-biphenyl]-4-yl)oxy]propyl,3-(2,3-difluorophenoxy)propyl, 3-(2,4-dibromophenoxy)propyl,3-(2,4-difluorophenoxy)propyl, 3-(2-methoxy-4-methylphenoxy)propyl,3-(4-iodo-2-methylphenoxy)propyl, 3-(2,5-difluorophenoxy)propyl,3-(2-chloro-5-methylphenoxy)propyl,3-(2-isopropyl-5-methylphenoxy)propyl, 3-(2,6-difluorophenoxy)propyl,3-(2,6-dichlorophenoxy)propyl, 3-(2,6-dimethylphenoxy)propyl,3-(2-fluoro-6-methylphenoxy)propyl, 3-hydroxypropyl,3-(2,3,6-trimethylphenoxy)propyl, 3-(mesityloxy)propyl,3-(2,6-dibromo-4-fluorophenoxy)propyl,3-(4-chloro-3-fluorophenoxy)propyl, 3-(4-chloro-3-methylphenoxy)propyl,3-(3-chloro-4-fluorophenoxy)propyl, 3-(1,3-benzodioxol-5-yloxy)propyl,3-(3,5-dichlorophenoxy)propyl, 3-(3,5-dimethylphenoxy)propyl,3-(3,5-dimethoxyphenoxy)propyl,3-(5,6,7,8-tetrahydro-1-naphthalenyloxy)propyl,3-[(2,4-dichloro-1-naphthyl)oxy]propyl,3-[4-methoxy-1-naphthyl)oxy]propyl, 3-[4-chloro-1-naphthyl)oxy]propyl,3-[1,6-dibromo-2-naphthyl)oxy]propyl, 3-[1-bromo-2-naphthyl)oxy]propyl,3-(2,3,4,5,6-pentafluorophenoxy)propyl, 3-(5-isoquinolinyloxy)propyl,2-methyl4-methoxyphenyl, 2-ethoxyphenyl, phenyl, phenoxy, 4-pyridinyl,4-methoxyphenyl, 3,5-difluorophenyl, 3-[ 1,1′-biphenyl]-2-yloxypropyl,chloro, 2,6-difluorophenyl, bromo, 2-methylphenyl, 2-methoxyphenyl,2-propoxyphenyl, 2-fluorophenyl, 2,4-dichlorophenyl,3-(2,4-dibromophenoxy)propyl, 3-(5-chloro-8-quinolinyloxy)propyl,fluoro, 2,6-difluorophenyl, 4-methoxy-2-methylphenyl, or2,4-dichlorophenyl.
 16. The compound of claim 1 wherein R⁴ is10-(2-ethoxyphenyl).
 17. The compound of claim 1 which is a compound ofFormula (II):

wherein p is 0, 1, 2, or 3; and R², R³, R⁴, Ar, and q are as defined inclaim 1; or a pharmaceutically acceptable salt thereof.
 18. The compoundof claim 1 which is a compound of Formula (III):

wherein R² and q are as defined as in claim 1; R⁸ is H or C₁₋₆alkyl, R⁹is H,C₁₋₆alkyl, C₁₋₆alkyl S—, or halo, and R¹⁰ is C₁₋₆alkyl orC₃₋₈cycloalkyl; or a pharmaceutically acceptable salt thereof.
 19. Thecompound: (5aS*,10bS*)-10-(2-ethoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole,(5aS, 10bS)-10-(2-ethoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole, (5aR,10bR)-10-(2-ethoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole,(5aS*,10bS*)-10-(2-butoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole,(5aS,10bS)-10-(2-butoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole,(5aR,10bR)-10-(2-butoxyphenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole,(5aS*, 10bS*)-10-[2-(cyclohexyloxy)phenyl]-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole,(5aS*,10bS*)-10-[2-(cyclobutyloxy)phenyl]-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole,(5aS*,10bS*)-10-[2-(trifluoromethoxy)phenyl]-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole,or(5aS*,10bS*)-10-(2-chlorophenyl)-1,2,3,4,5,5a,6,10b-octahydroazepino[4,5-b]indole;or a pharmaceutically acceptable salt thereof.
 20. A pharmaceuticalcomposition comprising a compound as described in claim 1 and apharmaceutically acceptable carrier.
 21. A method of treating a diseaseor disorder of the central nervous system in a mammal comprisingadministering to the mammal a pharmaceutically effective amount of acompound as described in claim
 1. 22. The method of claim 21 wherein thedisease or disorder is anxiety, depression, schizophrenia, epilepsy,migraine, Alzheimers disease, sleep disorders, obesity, a stress relateddisease, or withdrawal from drug abuse.
 23. The method of claim 21wherein the disease or disorder is anxiety, depression, epilepsy,migraine, obesity, a stress related disease, and withdrawal from drugabuse.
 24. A compound of Formula (I):

wherein: R¹ is selected from the group consisting of hydrogen,C₁₋₈alkyl, and C₁₋₈hydrocarbyleneAr; each R², independently, is selectedfrom the group consisting of C₁₋₈alkyl, and OH; R³ is hydrogen,C₁₋₈alkyl, Ar, Het, R⁷C(═O)—, R⁷OC(═O)—, R⁵R⁶NC(═O)—, R⁷C(═S)—,R⁷SC(═O)—, R⁵R⁶NC(═S)—, R⁷SO₂—, R⁵R⁶NSO₂—, R⁷S(═O)—, R⁵R⁶NS(═O)—,R^(c)C₁₋₈hydrocarbylene—, or R^(c)C₁₋₈hydrocarbyleneC(═O)—; each R⁴,independently, is selected from the group consisting of Ar, C₁₋₈alkyl,ArO—, C₁₋₈alkoxy, Het, halo, OH, CN, NO₂, CF₃, CF₃O, NR^(a)R^(b),N═CR^(a)R^(b), R⁷S, C₁₋₈hydrocarbyleneAr, and C₁₋₈hydrocarbyleneOR^(a);each R⁵ and R⁶ is independently hydrogen, C₁₋₈alkyl, C₂₋₈alkenyl,C₂₋₈alkynyl, haloC₁₋₈alkyl, C₃₋₈cycloalkenyl, Ar, or—C₁₋₈hydrocarbyleneAr; or R⁵ and R⁶ together with the nitrogen to whichthey are attached form a pyrrolidino, piperidino, morpholino, orthiomorpholino ring; each R⁷ is independently hydrogen, C₁₋₈alkyl,C₂₋₈alkenyl, C₂₋₈alkynyl, haloC₁₋₈alkyl, C₃₋₈cycloalkenyl, Ar, or—C₁₋₈hydrocarbyleneAr; R^(a) and R^(b), independently, are selected fromthe group consisting of hydrogen, C₁₋₈alkyl, Ar, C₁₋₃hydrocarbyleneAr,SO₂Ar, SO₂C₁₋₄alkyl, (C₃₋₈cycloalkyl)C₁₋₈alkylene, and Het; R^(c) is Ar,Het, R⁷CO₂—, R⁷C(═O)—, R⁷OC(═O)—, R⁷O—, R⁷C₁₋₈alkyleneO—, R⁷S—,R⁷C(═S)—, R⁷S(═O)—, R⁷S(═O)₂—, R⁷SC(═O)—, R⁷C(═O)N(R⁷)—, R⁷C(═S)N(R⁷)—,R⁵R⁶N—, R⁵R⁶NC(═O)—, R⁵R⁶NC(═S)—, R⁵R⁶NS(═O)—, R⁵R⁶NSO₂—, R⁷S(═O)N(R⁷)—,R⁷SO₂N(R⁷)—, or R⁷N(R⁷)C(═O) N(R⁷)—; each Ar is independently aryl orheteroaryl; p is 0, 1, 2, 3, or 4; and q is 0, 1, 2, 3, 4, 5, 6, 7, 8,9, or 10; wherein any Ar of R¹, R³-R⁷, R^(a), R^(b) and R^(c) isoptionally substituted with one or more substituents independentlyselected from halo, CN, NO₂, OR^(c), methylenedioxy, ethylenedioxy, CF₃,OCF₃, SR^(e), SO₂R^(e), NR^(f)R^(g), CONR^(f)R^(g), COR^(e), R^(e), andC₁₋₈hydrocarbyleneR^(d); each R^(d) is independently hydroxy,C₁₋₈alkoxy, cyano, SR^(h), or C(═O)R^(h); each R^(e) is independentlyselected from the group consisting of hydrogen, C₁₋₈alkyl, Ar,C₁₋₃hydrocarbyleneAr, SO₂Ar, SO₂C₁₋₄alkyl, (C₃₋₈cycloalkyl)C₁₋₈alkylene,and Het; wherein any Ar of R^(e) is optionally substituted with one ormore substituents independently selected from halo, CN, NO₂, OR^(d),methylenedioxy, ethylenedioxy, CF₃, OCF₃, SR^(f), SO₂R^(f), NR^(f)R^(g),CONR^(f)R^(g), COR^(f), R^(f), and C₁₋₈hydrocarbyleneR^(d); each R^(f)and R^(g), is independently selected from the group consisting ofhydrogen, C₁₋₈alkyl, Ar, C₁₋₃hydrocarbyleneAr, SO₂Ar, SO₂C₁₋₄alkyl,(C₃₋₈cycloalkyl)C₁₋₈alkylene, and Het; and each R^(h) is independentlyhydrogen, C₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, haloC₁₋₈alkyl,C₃₋₈cycloalkenyl, phenyl, or —C₁₋₈hydrocarbylene(phenyl); or apharmaceutically acceptable salt thereof; provided that when (a) R¹ ismethyl; and (b) R³ is hydrogen or —(CH₂)₃NR⁵R⁶, wherein R⁵ and R⁶ areeach methyl; then either (i) p is not 0 and at least one R⁴ is Ar, ArO—,C₁₋₈alkoyl, Het, halo, OH, CN, NO₂, CF₃, CF₃O, NR^(a)R^(b),N═CR^(a)R^(b), R⁷S—, C₁₋₈hydrocarbyleneAr, or C₁₋₈hydrocarbyleneOR^(a);or (ii) q is not 0 and at least one R² is OH.
 25. The compound of claim24 wherein R₁ is hydrogen.
 26. The compound of claim 24 wherein q is 2,3, or
 4. 27. The compound of claim 24 wherein q is
 1. 28. The compoundof claim 24 wherein q is
 0. 29. The compound of claim 24 wherein R³ ishydrogen, C₁₋₈alkyl, R⁵R⁶NC(═O)CH₂—, R⁷SC₁₋₈alkylene, or aryloxy(CH₂)₂—.30. The compound of claim 24, wherein R³ is hydrogen.
 31. The compoundof claim 24 wherein R³ is C₁₋₈alkyl, R⁵R⁶NC(═O)CH₂— or aryloxy(CH₂)₂—.32. The compound of claim 24 wherein R³ is: 2-(3-methoxyphenoxy)ethyl,2-(3-nitrophenoxy)ethyl, 2-(3-isopropylphenoxy)ethyl,2-(4-pyridyloxy)ethyl, 3-phenoxypropyl, 3-(3-chlorophenoxy)propyl,3-(4-fluorophenoxy)propyl, 2-phenoxyethyl,N-(2,3-dimethylphenyl)amino-carbonylmethyl,N-(3-methylphenyl)aminocarbonylmethyl,N-(2-fluoro-4-methylphenyl)aminocarbonylmethyl,N-mesitylaminocarbonylmethyl, N-(4-methoxyphenyl)aminocarbonylmethyl,N-(phenyl)aminocarbonylmethyl, N-(4-fluorophenyl)aminocarbonylmcthyl,N-(3-nitrophenyl)aminocarbonylmethyl,N-(3-methoxyphenyl)aminocarbonylmethyl,N-(4-cyanophenyl)aminocarbonylmethyl,N-(3,5-dimethoxyphenyl)aminocarbonylmethyl,N-(2,4-dimethoxyphenyl)aminocarbonylmethyl,N-(3-chloro-4-fluorophenyl)aminocarbonylmethyl, 2-anilinoethyl,1H-benzimidazol-2-ylmethyl, isobutoxycarbonylmethyl, carboxymethyl,N,N-dimethylaminocarbonylmethyl, aminocarbonylmethyl,2-(phenylsulfinyl)ethyl, 2-(phenylsulfonyl)ethyl, 2-hydroxyethyl,2-(4-chlorophenoxy)ethyl, 2-(4-fluorophenoxy)ethyl, 2-(phenylthio)ethyl,2-aminoethyl, 2-(anilinocarbonylamino)-ethyl, 2-(benzoylamino)ethyl,2-(phenylsulfonylamino)ethyl, N-(4-methoxyphenyl)aminocarbonylethyl,N-phenylaminocarbonylmethyl, N-(2-pyridyl)aminocarbonylmethyl,N-(4-methoxyphenyl)aminocarbonylmethyl,N-(2,3-dimethylphenyl)aminocarbonylmethyl,N-(5,6,7,8-tetrahydro-1-naphthalenyl)aminocarbonylmethyl,3-ethylanilinocarbonylmethyl, 3-isopropylanilinocarbonylmethyl,N-(3-tert-butylphenyl)aminocarbonylmethyl,N-(1,3-benzothiazol-2-yl)aminocarbonylmethyl,N-(4-methyl-1,3-thiazol-2-yl)aminocarbonylmethyl,N-(5-methyl-1,3-thiazol-2-yl)aminocarbonylmethyl,N-(4-tert-butyl-1,3-thiazol-2-yl)aminocarbonylmethyl,N-(4-phenyl-1,3-thiazol-2-yl)aminocarbonylmethyl, 3-pbenylpropyl,2-phenoxyethyl, 2-(4-chlorophenoxy)ethyl, 2-(4-fluorophenoxy)ethyl,2-(5,7-dibromo-8-quinolinyloxy)ethyl, 2-(8-quinolinyloxy)ethyl,2-(5-isoquinolinyloxy)ethyl, 2-(5-quinolinyloxy)ethyl,2-(5,6,7,8-tetrahydro-1-naphthalenyloxy)ethyl,2-(1,3-benzodioxol-5-yloxy)ethyl, 2-(1H-indol-4-yloxy)ethyl,2-(5,6,7,8-tetrahydro-2-naphthalenyloxy)ethyl, 2-(7-quinolinyloxy)ethyl,2-[(5,5-dimethyl-5,6,7,8-tetrahydronaphthalen-1-yl)oxy]ethyl,N-(3-chloro-2-methylphenyl)aminocarbonylmethyl,N-[2-methyl-3-(trifluoromethyl)phenyl]aminocarbonylmethyl,N-(5,6,7,8-tetrahydronaphthalen-1-yl)aminocarbonylmethyl,N-(4-methyl-1,3-thiazol-2-yl)aminocarbonylmethyl,N-(1,3-dihydro-2-benzofuran-4-yl)aminocarbonylmethyl,N-(4-methoxyphenyl)aminocarbonylmethyl,N-(3-pyridyl)aminocarbonylmethyl,N-(4-methyl-1,3-thiazol-2-yl)aminocarbonylmethyl, or2-(5,6,7,8-tetrahydronaphthalen-1-yloxy)ethyl.
 33. The compound of claim24 wherein p is 1, 2, or
 3. 34. The compound of claim 24 wherein p is 0.35. The compound of claim 24 wherein R⁴ is phenyl, optionallysubstituted at the 2-position of the phenyl.
 36. The compound of claim24 wherein R⁴ is 2-ethoxyphenyl, or 2-chlorophenyl.
 37. The compound ofclaim 24 wherein R⁴ is aryl, substituted at the 10-position of formula(I).
 38. The compound of claim 24 wherein R⁴ is: 5-pyrimidinyl,3,4-dimethoxyphenyl, 3,5-difluorophenyl, 4-n-butyloxyphenyl,4-trifluoromethoxyphenyl, 3,4-dichlorophenyl, 2-naphthyl, 4-pyridinyl,bromo, benzhydrilideneamino, amino, N-(phenylsulfonyl)amino, phenoxy,3-(phenoxy)propyl, 3-(2-naphthyloxy)propyl, 3-(1-naphthyloxy)propyl,3-([1,1′-biphenyl]-4-yloxy)propyl, 3-(3-methoxyphonoxy)propyl,3-(4-methoxyphenoxy)propyl, 3-(4-chlorophenoxy)propyl,3-(3-chlorophenoxy)propyl, 3-(2-chlorophenoxy)propyl,3-(2,4-dichlorophenoxy)propyl, 3-(2,5-dichlorophenoxy)propyl,3-(4-fluorophenoxy)propyl, 3-(4-methylphenoxy)propyl,3-(4-cyanophenoxy)propyl, 3-(pyridin-2-yloxy)propyl,3-(2-bromophenoxy)propyl, 3-(2-iodophenoxy)propyl,3-(2-ethylphenoxy)propyl, 3-(2-isopropylphenoxy)propyl,3-(2-cyanophenoxy)propyl, 3-(pyridin-3yloxy)propyl,3-(3-fluorophenoxy)propyl, 3-(3-bromophenoxy)propyl,3-(3-iodophenoxy)propyl, 3-(3-isopropylphenoxy)propyl,3-[3-(trifluoromethyl)phenoxy]propyl,3-[3-(trifluoromethoxy)phenoxy]propyl, 3-(3-ethylphenoxy)propyl,3-(3-tert-butylphenoxy)propyl, 3-(pyridin-4yloxy)propyl,3-(4-methoxyphenoxy)propyl, 3-[4-(benzyloxy)phenoxy]propyl,3-(4-bromophenoxy)propyl, 3-(4-iodophenoxy)propyl,3-(4-ethylphenoxy)propyl, 3-(4-tert-butylphenoxy)propyl,3-[4′-(bromo[1,1′-biphenyl]-4-yl)oxy]propyl,3-(2,3-difluorophenoxy)propyl, 3-(2,4-dibromophenoxy)propyl,3-(2,4-difluorophenoxy)propyl, 3-(2-methoxy-4-methylphenoxy)propyl,3-(4-iodo-2-methylphenoxy)propyl, 3-(2,5-difluorophenoxy)propyl,3-(2-chloro-5-methylphenoxy)propyl,3-(2-isopropyl-5-methylphenoxy)propyl, 3-(2,6-difluorophenoxy)propyl,3-(2,6-dichlorophenoxy)propyl, 3-(2,6-dimethylphenoxy)propyl,3-(2-fluoro-6-methylphenoxy)propyl, 3-hydroxypropyl,3-(2,3,6-trimethylphenoxy)propyl, 3-(mesityloxy)propyl,3-(2,6-dibromo-4-fluorophenoxy)propyl,3-(4-chloro-3-fluorophenoxy)propyl, 3-(4-chloro-3-methylphenoxy)propyl,3-(3-chloro-4-fluorophenoxy)propyl, 3-(1,3-benzodioxol-5-yloxy)propyl,3-(3,5-dichlorophenoxy)propyl, 3-(3,5-dimethylphenoxy)propyl,3-(3,5-dimethoxyphenoxy)propyl,3-(5,6,7,8-tetrahydro-1-naphthalenyloxy)propyl,3-[(2,4-dichloro-1-naphthyl)oxy]propyl,3-[4-methoxy-1-naphthyl)oxy]propyl, 3-[4-chloro-1-naphthyl)oxy]propyl,3-[1,6-dibromo-2-naphthyl)oxy]propyl, 3-[1-bromo-2-naphthyl)oxy]propyl,3-(2,3,4,5,6-pentafluorophenoxy)propyl, 3-(5-isoquinolinyloxy)propyl,2-methyl-4-methoxyphenyl, 2-ethoxyphenyl, phenyl, phenoxy, 4-pyridinyl,4-methoxyphenyl, 3,5-difluorophenyl, 3-[1,1′-biphenyl]-2-yloxypropyl,chloro, 2,6-difluorophenyl, bromo, 2-methylphenyl, 2-methoxyphenyl,2-propoxyphenyl, 2-fluorophenyl, 2,4-dichlorophenyl,3-(2,4-dibromophenoxy)propyl, 3-(5-chloro-8-quinolinyloxy)propyl,fluoro, 2,6-difluorophenyl, 4-methoxy-2-methylphenyl, or2,4-dichlorophenyl.
 39. The compound of claim 24 wherein R⁴ is10-(2-ethoxyphenyl).
 40. A pharmaceutical composition comprising acompound as described in claim 24 and a pharmaceutically acceptablecarrier.
 41. A method of treating anxiety, depression, epilepsy,migraine, or obesity in a mammal comprising administering to the mammala pharmaceutically effective amount of a compound as described in claim24.
 42. The method of claim 41 wherein the disease or disorder isanxiety or depression.